Compounds and adjuvant preparations useful for pneumococcal vaccines

Abstract

To provide novel compounds and formulations useful for pneumococcal and pneumococcal conjugate vaccines. [Solution] An immunogenic composition comprising at least one Streptococcus pneumoniae polysaccharide carrier protein conjugate and a stable nanoemulsion compound exemplified by N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3,5-dimethoxyphenyl)piperazin-1-yl)-5-oxopentyl)stearamide (compound A-1).

Description

[Technical Field]

[0001] Cross-reference of related applications This application is based on U.S. Provisional Patent Application No. 63 / 503,021, filed on 18 May 2023. The interests of the Specification No. are asserted, and its entire contents are incorporated herein by reference. [Background technology]

[0002] Pneumococcal disease is caused by the bacterium Streptococcus pneumoniae. It is caused by infection with Streptococcus pneumoniae (AE). Different serotypes of Streptococcus pneumoniae are known to cause different symptoms of the disease, and infections can be This can lead to a range of symptoms, from ear and sinus infections to pneumonia and bloodstream infections. Pneumococcal disease has a high associated morbidity and mortality rate worldwide, particularly among the elderly and children. It possesses. Currently, there are 100 capsular polysaccharides (some of which define or specify a particular serotype). (Used for this purpose) has been identified (Ganaie, F. et al. (2020) Cl inical Science and Epidemiology,Vol.11,I (Issue 3, pages 1-15). These serotypes, their chemical structure, serology They are distinguished by specific responses and other related gene mutations.

[0003] In 1983, PNEUMOVAX®, a 23-valent pneumococcal vaccine (PV), was introduced. Approved in the United States by Merck & Co., Inc. (Loway, New Jersey, USA) This vaccine reduces immunogenicity in infants due to a T-cell-independent response. It has been proven. To address this problem, especially in infants, the pneumococcal conjugate vaccine PCV was developed. By covalently bonding polysaccharides to a carrier protein, immunity The virulence response became T cell-dependent. In 2000, PREVNAR, a 7-valent PCV (registered (Trademark) (Pfizer Inc. (Philadelphia, Pennsylvania, USA)) Approved in 2010 as PREVNAR13 (registered trademark) (PFI), a 13-valent PCV. VAXNEU (Zer Inc.) was approved in the United States in 2021. VANCE (Registered Trademark) (Merck & Co., Inc., New Jersey, USA) Pfizer's PREVNAR20® (registered trademark), which is a 20-valent PCV. (Inc.) was approved in the United States. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Ganaie,F.et al.(2020)Clinical Science and Epidemiology,Vol.11,Issue 3,pages 1-15 [Overview of the project] [Problems that the invention aims to solve]

[0005] Approved PCV now uses aluminum as an adjuvant to enhance immunogenicity. It utilizes the contained derivatives. The aluminum adjuvant has shown immunogenicity from baseline. While it increases the response, the immunogenic response is more pronounced in infants with higher binding titers of PCV. It is unclear whether this is sufficient. Therefore, the current aluminum adjuvant standard We need to identify other adjuvants that can increase the immunogenicity of polyvalent PCV more effectively. There is. [Means for solving the problem]

[0006] The present invention relates to (i) one or more Streptococcus pneumoniae antigens and (i i) One or more of the following equations: I, Ia, II, IIa, III, IIIa, IV, or IVa (iii) a compound, or (one or more) pharmaceutically acceptable salt thereof With regard to formulations and compositions comprising a carrier, one or more Streptococcus pneumoniae antigens are present in pneumonia. It can induce an immune response against one or more serotypes of streptococcus.

[0007] The present invention also comprises (i) one or more Streptococcus pneumoniae polysaccharide carrier protein conjugates Each of the conjugates is conjugated to a specific pneumonia chain on a carrier protein. One or more Streptococcus pneumoniae cells containing polysaccharides of the coccus serotype and whose carrier protein is CRM197. Bacterial polysaccharide carrier protein conjugates and (ii) formulas I, Ia, II, IIa, III, One or more compounds of type IIIa, IV, or IVa, or (one or more) such drugs Formulations and compositions comprising (iii) a pharmaceutically acceptable salt and (iii) a pharmaceutically acceptable carrier. This invention relates to the prevention of pneumococcal disease or to the treatment of Streptococcus pneumoniae. (i) One or more Streptococcus pneumoniae polysaccharide carriers for the prevention or reduction of the possibility of infection It is a protein conjugate, and each conjugate is conjugated to a carrier protein. It contains polysaccharides of a specific serotype of Streptococcus pneumoniae, and the carrier protein is CRM197. (ii) Formula I, Ia , one or more compounds of type II, IIa, III, IIIa, IV or IVa, or ( one or more pharmaceutically acceptable salts thereof, and (iii) a pharmaceutically acceptable carrier , relates to the use of a preparation or composition comprising the foregoing.

[0008] The present invention also relates to (i) one or more Streptococcus pneumoniae antigens, (ii) a compound of formula I, Ia, II, I Ia, III, IIIa, IV or IVa, or one or more pharmaceutically acceptable salts thereof, (iii) one or more sorbitan-based surfactants, and (iv) one or more te rpene, and preparations and compositions comprising the foregoing. In some embodiments, one or more pneumococcal coccal antigens are Streptococcus pneumoniae polysaccharide-carrier protein conjugates, wherein the conjugate each comprises a polysaccharide of a specific Streptococcus pneumoniae serotype conjugated to a carrier protein In some embodiments, the carrier protein is CRM197. In some embodi In an embodiment, the Streptococcus pneumoniae antigen is a polysaccharide-carrier protein conjugate, and the polysaccharide is serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, and the carrier protein is CRM197. In some embodiments , the Streptococcus pneumoniae antigen is a polysaccharide-carrier protein conjugate, and the polysaccharide is of serotype 1 , 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, and the carrier protein is CRM197. In some embodi In an embodiment, the Streptococcus pneumoniae antigen is a polysaccharide-carrier protein conjugate, and the polysaccharide is serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, It consists of and 35B, and the carrier protein is CRM197. In some embodiments The pneumococcal antigen is a polysaccharide-carrier protein conjugate, and the polysaccharide is serotype 1 , 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, It consists of 33F and 35B, and the carrier protein is CRM197. In terms of application, the Streptococcus pneumoniae antigen is a polysaccharide-carrier protein conjugate, and the polysaccharide is Serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 16F, 18C, 19A, 19F, 22F, 23A, It consists of 23B, 23F, 24F, 33F, and 35B, and the carrier protein is CRM1 97. In some embodiments, the pneumococcus antigen is a polysaccharide carrier protein condyl It is a polysaccharide, and is found in serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, and 10A. , 11A, 12F, 14, 15A, 15C, 16F, 18C, 19A, 19F, 22F, It consists of 23A, 23B, 23F, 24F, 33F, and 35B, and the carrier protein is, It's a CRM197.

[0009] The present invention also includes (i) one or more Streptococcus pneumoniae antigens and (ii) formulas I, Ia, II, I One or more compounds of type Ia, III, IIIa, IV, or IVa, or their pharmaceutically appropriate (iii) permissible salts, (iii) sorbitan trioleate (SPAN-85), and (iv) Polysorbate-20 (PS-20) or Polysorbate-80 (PS-80), and ( v) The present invention relates to formulations and compositions containing squalene. In some embodiments, one or more The above Streptococcus pneumoniae antigen is a Streptococcus pneumoniae polysaccharide carrier protein conjugate, Each jugate is conjugated to a specific Streptococcus pneumoniae serotype of carrier protein. It contains polysaccharides. In some embodiments, the carrier protein is CRM197. In several embodiments, the Streptococcus pneumoniae antigen is a polysaccharide carrier protein conjugate, Polysaccharides are found in serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, and 12F. , 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, It consists of 33F and 35B, and the carrier protein is CRM197. In terms of application, the Streptococcus pneumoniae antigen is a polysaccharide-carrier protein conjugate, and the polysaccharide is Serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18C, 19A, 19F, 22F, 23B, 23F, It consists of 24F, 33F, and 35B, and the carrier protein is CRM197. In several embodiments, the Streptococcus pneumoniae antigen is a polysaccharide carrier protein conjugate, Polysaccharides are found in serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, and 12F. , 14, 15A, 15C, 18C, 19A, 19F, 22F, 23B, 23F, 24F, It consists of 33F and 35B, and the carrier protein is CRM197. In terms of application, the Streptococcus pneumoniae antigen is a polysaccharide-carrier protein conjugate, and the polysaccharide is Serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, and the carrier protein is CRM197. In some embodiments, the Streptococcus pneumoniae antigen is a polysaccharide-carrier protein conjugate, and the polysaccharides consist of serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F , 14, 15A, O-deacetylated 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, and the carrier protein is CRM197. In some embodiments, the Streptococcus pneumoniae antigen is a polysaccharide-carrier protein conjugate, and the polysaccharides consist of serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, 15C, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, and the carrier pro tein is CRM197.

[0010] The present invention also relates to a composition comprising the pneumococcal conjugate disclosed herein and a stable nanoemulsi on "SNE". As an example, a specific SNE comprises N-(5- 4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyri midin-2-yl)methyl)-3,5-dimethoxyphenyl)piperazin-1-yl) -5-oxopentyl)stearamide, also known as "Compound A-1". This specific SNE is referred to as Compound A-1-SNE, and comprises i) Compound A-1, ii) sorbitan triolea te (SPAN-85), (iii) polysorbate 20 (PS-20) or polysorb ate 80 (PS-80), and (iv) squalene. As another example, the specific SNE is N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyra Zolo[4,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl(piperazi) This contains 1-yl-5-oxopentyl stearamide, also known as "compound B-1". The specific SNE is called compound B-1-SNE, i) compound B-1, ii) SPAN -85, (iii) PS-20 or PS-80, and (iv) squalene. As an example, certain SNEs include N-(4-((4-((5-amino-7-(butylamino )-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3,5-dimethyl Contains cybenzyl(methyl)amino(butyl)stearamide, also known as "compound C-4". This particular SNE is called compound C-4-SNE, i) compound C-4, ii) SPA (iii) PS-20 or PS-80, and (iv) squalene.

[0011] The present invention also relates to pneumococcal polysaccharides or pneumococcal conjugates, as disclosed herein. This relates to an immunogenic composition containing SNE.

[0012] The present invention also provides a solution to a patient who requires the immunogenic composition of the present invention to be administered to the patient. This concerns methods for treating or preventing pneumococcal disease in patients.

[0013] The present invention also includes administering the immunogenic composition of the present invention to a patient in need thereof. Regarding methods to prevent or reduce the likelihood of infection by one or more serotypes of Streptococcus pneumoniae. do. [Brief explanation of the drawing]

[0014] [Figure 1](Example 10) This figure shows the OD640 readouts after incubation of human TLR7 (upper panel) or TLR8 (lower panel) expressing HEK-Blue® 293 cells (InvivoGen) with different concentrations of compound B-1-SNE. The Y axis represents the total concentration of compound B-1-SNE. [Figure 2] (Example 11) This figure shows the anti-6B IgG titers before immunization (day 0, pooled serum), post-dose 1 (day 21), post-dose 2 (day 42), and post-dose 3 (day 70) after immunizing mice with the formulations listed in Table 7. Error bars are geometric mean with 95% confidence intervals. Transformed data analyzed by one-way ANOVA with Dunnett post-hoc test, *p<0.05. [Figure 3] (Example 11) This figure shows the anti-6B OPA titers from pooled serum of mice immunized with the formulations listed in Table 7, before immunization (day 0), after dose 1 (day 21), after dose 2 (day 42), and after dose 3 (day 70). [Figure 4] (Example 12) This figure shows the ratio of serotype-specific IgG titers in infant rhesus monkeys after immunization with PCV24 containing compound B-1-SNE (compound B-1 at a 150 μg dose), PCV24 containing compound B-1-SNE (compound B-1 at a 50 μg dose), and PCV24 containing compound B-1-SNE (compound B-1 at a 15 μg dose), compared to immunization with PCV24 formulated without adjuvant 3 doses post-dose. Data for serotypes 6C and 15B are included to assess cross-reactivity. [Figure 5] (Example 12) This figure shows the ratio of serotype-specific IgG titers in infant rhesus monkeys after immunization with PCV24 containing compound B-1-SNE (compound B-1 at a dose of 150 μg), PCV24 containing compound B-1-SNE (compound B-1 at a dose of 50 μg), and PCV24 containing compound B-1-SNE (compound B-1 at a dose of 15 μg), compared to immunization with PCV24 formulated with post-dose APA. Data for serotypes 6C and 15B are included to assess cross-reactivity. [Figure 6](Example 12) This figure shows the ratio of serotype-specific IgG titers in infant rhesus monkeys after immunization with PCV24 containing compound B-1-SNE (compound B-1 at a dose of 150 μg), PCV24 containing compound B-1-SNE (compound B-1 at a dose of 50 μg), and PCV24 containing compound B-1-SNE (compound B-1 at a dose of 15 μg), compared to immunization with PCV20 3 post-dose. [Figure 7] (Example 13) This figure shows the ratio of serotype-specific IgG titers in infant rhesus monkeys after immunization with PCV24 containing compound B-1-SNE (100 μg dose of compound B-1), PCV24 containing compound B-1-SNE (10 μg dose of compound B-1), PCV24 containing compound B-1-SNE (1 μg dose of compound B-1), and PCV24 containing compound B-1-SNE (0.1 μg dose of compound B-1), compared with immunization with PCV20 3 doses later. [Figure 8] (Example 14) This figure shows the ratio of serotype-specific IgG titers in mice immunized with PCV26 containing compound B-1-SNE (compound B-1 at a 10 μg dose) compared to immunization with PCV26 formulated with post-dose APA. Data for serotypes 6C and 15B are included to assess cross-reactivity. [Figure 9] (Example 14) This figure shows the IgG2a / IgG1 titer ratio of serotype-specific antibodies in mice immunized with PCV26 containing compound B-1-SNE (compound B-1 at a dose of 10 μg) or PCV26 formulated with post-dose APA 3. Responses from three representative serotypes 18C, 19F, and 24F are shown (from left to right). [Figure 10A] (Example 14) This figure shows that mice immunized with PCV26 containing compound B-1-SNE (compound B-1 at a dose of 10 μg) or PCV26 formulated with APA were protected from intratracheal challenge by Streptococcus pneumoniae 24F. Bacteremia was quantified 24 hours after infection with serotype 24F bacteria and expressed as log CFU / mL. [Figure 10B](Example 14) This figure shows that mice immunized with PCV26 containing compound B-1-SNE (compound B-1 at a dose of 10 μg) or PCV26 formulated with APA were protected from intratracheal challenge by Streptococcus pneumoniae 24F. Survival rates were evaluated over approximately 240 hours after infection with serotype 24F bacteria. [Modes for carrying out the invention]

[0015] The present invention involves one or more Streptococcus pneumoniae antigens and a compound having the structure described in Formula I: [ka] (In the formula, R a H, -OH, (C1-C6)alkyl, (C1-C6)alkenyl, (C1- C6) Alkynyl, -O(C1-C6) alkyl, -O(C1-C6) alkenyl, -O (C1-C6) Selected from alkynyl, chlorine, fluorine, and -NR'R'', the above ( C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, -O( C1-C6) alkyl, -O(C1-C6) alkenyl, and -O(C1-C6) Quinyl is -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O (C1-C4) 1 to independently selected from the group consisting of alkynyl, chlorine, and fluorine It may also be substituted with four substituents. R a’ is H, -OH, (C1-C6)alkyl, (C1-C6)alkenyl, (C1 -C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C6)alkenyl, - Selected from O(C1-C6)alkynyl, chlorine, fluorine, and -NR'R'', (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O (C1-C6)alkyl, -O(C1-C6)alkenyl, and -O(C1-C6) Lukinyl is -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, - One independently selected from the group consisting of O(C1-C4)alkynyl, chlorine, and fluorine. It may also be substituted with up to 4 substituents. R a’’ H, -OH, (C1-C6)alkyl, (C1-C6)alkenyl, (C 1-C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C6)alkenyl, Selected from -O(C1-C6)alkynyl, chlorine, fluorine, and -NR'R'', prior Note (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, - O(C1-C6) alkyl, -O(C1-C6) alkenyl, and -O(C1-C6) Alkinyls are -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, Independently selected from the group consisting of -O(C1-C4)alkynyl, chlorine, and fluorine. It may be substituted with 1 to 4 substituents. R' and R'' are H, (C1-C6) alkyl, (C1-C6) alkenyl, and A (C1-C6) alkyl, (C) is independently selected from (C1-C6)alkynyl. (C1-C6) alkenyls and (C1-C6) alkynyls are -OH, -O(C1-C4 )alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, It may also be substituted with 1 to 4 substituents independently selected from the group consisting of fluorine. , or R' and R'' together with the nitrogen they are bound to, bonded together This forms a (C3-C6) heterocycloalkyl, and the (C3-C6) heterocycloalkyl Lukil is -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O (C1-C4) 1 to independently selected from the group consisting of alkynyl, chlorine, and fluorine It may also be substituted with four substituents. R b Each appearance is H, -OH, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C6)alkene Independently from -O(C1-C6)alkynyl, chlorine, fluorine, or NR'R'' Selected, the (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) Lukinyl, -O(C1-C6)alkyl, -O(C1-C6)alkenyl, and -O( C1-C6) alkynyls are -OH, -O(C1-C4) alkyl, -O(C1-C4) Independently from the group consisting of alkenyls, -O(C1-C4)alkynyls, chlorine, and fluorine It may be substituted with 1 to 4 substituents selected by: A is (C1-C6) alkyl, (C3-C6) heterocycloalkyl, heterocyclo Alkyl-C(O)-R z -, (C1-C4)alkyl-N(R z )-R z -, Ariel A carbon or nitrogen bond spacer selected from, and heteroaryls, wherein (C (1-C6) alkyl, (C3-C6) heterocycloalkyl, aryl, and hetero The reel is -OH, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6 )Alkynyl, -O(C1-C6)alkyl, -O(C1-C6)alkenyl, -O(C 1-C6) Independently selected from the group consisting of alkynyl, chlorine, fluorine, and NR'R'' may be substituted with 1 to 6 substituents, said (C1-C6)alkyl, (C1 -C6)alkenyl, (C1-C6)alkynyl, -O(C1-C6)alkyl, -O( C1-C6)alkenyl, and -O(C1-C6)alkynyl are substituted with -OH, -O(C1 -C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlor ine, and fluorine, and may be substituted with 1 to 6 substituents independently selected from the group consisting of and optionally, R z at each occurrence is independently H or (C1-C6)alkyl, B is

Chemical

Chemical

[0016] The present invention involves one or more Streptococcus pneumoniae antigens and a compound having the structure described in formula Ia: [ka] (In the formula, R' and R'' are H, (C1-C6) alkyl, (C1-C6) alkenyl, and A (C1-C6) alkyl, (C) is independently selected from (C1-C6)alkynyl. (C1-C6) alkenyls and (C1-C6) alkynyls are -OH, -O(C1-C4 )alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, It may also be substituted with 1 to 4 substituents independently selected from the group consisting of fluorine. , or R' and R'' together with the nitrogen they are bound to, bonded together This forms a (C3-C6) heterocycloalkyl, and the (C3-C6) heterocycloalkyl Lukil is -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O (C1-C4) 1 to independently selected from the group consisting of alkynyl, chlorine, and fluorine It may also be substituted with four substituents. R bEach occurrence is -O(C1-C4)alkyl, and the aforementioned -O(C1-C4)alkyl The letters are -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C 1-C4) One independently selected from the group consisting of alkynyl, chlorine, and fluorine. The substituents may be substituted with two substituents. A is [ka] Selected from, R z Each occurrence is independently either H or (C1-C6) alkyl. R d Each occurrence is -OH, (C1-C4)alkyl, -O(C1-C4)alkyl, salt Selected independently from elements and fluorine, B is [ka] And, D is [ka] A lipid chain selected from, where any carbon on the lipid chain is -OH, -O(C1-C4) Alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, if It may be substituted with fluorine, [ka] It is cis or trans stereochemistry, X 1 is -O-, -C(R) 2 -, or -NR- Each appearance of R is H, (C1-C4)alkyl, (C1-C4)alkenyl, (C1-C 4) Alkynyl, -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl Independently selected from -O(C1-C4)alkynyl, chlorine, and fluorine, m is 0, 1, or 2. n is 0, 1, 2, or 3. p is 0, 1, or 2. q is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9. s is 1, 2, 3, 4, 5, 6, 7, or 8. t is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or (18 years old) The present invention provides a composition comprising either or a pharmaceutically acceptable salt thereof.

[0017] The present invention involves one or more Streptococcus pneumoniae antigens and a compound having the structure described in Formula II: [ka] (In the formula, R 1 is a (C1-C6) alkyl group, and the (C1-C6) alkyl group has -OH group It may be substituted with 1 to 4 substituents independently selected from -O(CH3), R 2 is H, methyl, or -O(CH3), R 3 Each occurrence is independently H, (C1-C4) alkyl, and (C1-C4) alkenyl. , (C1-C4)alkynyl, or -O(C1-C4)alkyl, and the above (C1 -C4)alkyl, (C1-C4)alkenyl, (C1-C4)alkynyl, or - O(C1-C4) alkyl is one that can be independently selected from -OH and -O(CH3). Alternatively, it may be substituted with two substituents. R 4 Each occurrence is independently H, (C1-C4) alkyl, and (C1-C4) alkenyl. , (C1-C4)alkynyl, or -O(C1-C4)alkyl, and the above (C1 -C4)alkyl, (C1-C4)alkenyl, (C1-C4)alkynyl, or - O(C1-C4) alkyl is one that can be independently selected from -OH and -O(CH3). Alternatively, it may be substituted with two substituents. R 5 teeth, [ka] And, R 6 (C6-C 20 ) alkyl, (C6-C 20 ) alkenyl, and (C6-C 20 ) Selected from alkynyl, and the above (C6-C 20 ) alkyl, (C6-C 20 ) Al Kenil, and (C6-C 20 Alkynyl is -OH, -O(C1-C4)alkyl, -O(C1-C4) alkenyl, -O(C1-C4) alkynyl, chlorine, and fluorine They may be substituted with 1 to 6 substituents that are independently selected. Each occurrence of n is 4. The present invention provides a composition comprising either or a pharmaceutically acceptable salt thereof.

[0018] The present invention involves one or more Streptococcus pneumoniae antigens and a compound having the structure described in formula IIa: [ka] (In the formula, R 1 is butyl, and the butyl may be substituted with one or two -OH groups. often, R 3 Each occurrence is independently either H or -O(CH3), R 5 teeth, [ka] And, R 6 is, (C 10 -C 20 ) alkyl, (C 10 -C 20 ) alkenyl, and (C1 0-C 20 (Selected from Alkinil) The present invention provides a composition comprising either or a pharmaceutically acceptable salt thereof.

[0019] The present invention involves one or more Streptococcus pneumoniae antigens and a compound having the structure described in Formula III: [ka] (In the formula, R 1 is a (C1-C6) alkyl group, and the (C1-C6) alkyl group has -OH group It may be substituted with 1 to 4 substituents independently selected from -O(CH3), R 2 is H, methyl, or -O(CH3), R 3 Each occurrence is independently H, (C1-C4) alkyl, and (C1-C4) alkenyl. , (C1-C4)alkynyl, or -O(C1-C4)alkyl, and the above (C1 -C4)alkyl, (C1-C4)alkenyl, (C1-C4)alkynyl, or - O(C1-C4) alkyl is one that can be independently selected from -OH and -O(CH3). Alternatively, it may be substituted with two substituents. R 4 (C6-C 20 ) alkyl, (C6-C 20 ) alkenyl, and (C6-C 20 ) Selected from alkynyl, and the above (C6-C 20 ) alkyl, (C6-C20 ) Al Kenil, and (C6-C 20 Alkynyl is -OH, -O(C1-C4)alkyl, -O(C1-C4) alkenyl, -O(C1-C4) alkynyl, chlorine, and fluorine They may be substituted with 1 to 6 substituents that are independently selected. n is 4. The present invention provides a composition comprising either or a pharmaceutically acceptable salt thereof.

[0020] The present invention involves one or more Streptococcus pneumoniae antigens and a compound having the structure described in formula IIIa: [ka] During the ceremony, (R 1 is butyl, and the butyl is substituted with one or two -OH groups. Also, R 3 Each occurrence is independently either H or -O(CH3), R 4 is, (C 10 -C 20 ) alkyl, (C 10 -C 20 ) alkenyl, and (C1 0-C 20 (Selected from Alkinil) The present invention provides a composition comprising either or a pharmaceutically acceptable salt thereof.

[0021] The present invention involves one or more Streptococcus pneumoniae antigens and a compound having the structure described in Formula IV: [ka] During the ceremony, (R 1 is a (C1-C6) alkyl group, and the (C1-C6) alkyl group has -OH It may also be substituted with 1 to 4 substituents independently selected from -O(CH3), R2 is H, methyl, or -O(CH3), R 3 Each occurrence is independently H, (C1-C4) alkyl, and (C1-C4) alkenyl. , (C1-C4)alkynyl, or -O(C1-C4)alkyl, and the above (C1 -C4)alkyl, (C1-C4)alkenyl, (C1-C4)alkynyl, and -O (C1-C4) alkyl is one that can be independently selected from -OH and -O(CH3). Alternatively, it may be substituted with two substituents. R 4 Each occurrence is (C6-C 20 ) alkyl, (C6-C 20 ) Alkenil, and ( C6-C 20 ) independently selected from alkynyl, and the (C6-C 20 ) alkyl, (C 6-C 20 ) alkenyl, and (C6-C 20 Alkinyl is -OH, -O(C1- C4) alkyl, -O(C1-C4) alkenyl, -O(C1-C4) alkynyl, chlorine Alternatively, it may be substituted with 1 to 6 substituents independently selected from fluorine. n is 4. The present invention provides a composition comprising either or a pharmaceutically acceptable salt thereof.

[0022] The present invention involves one or more Streptococcus pneumoniae antigens and a compound having the structure described in formula IVa: [ka] (In the formula, R 1 is butyl, and the butyl may be substituted with one or two -OH groups. often, R 3 Each occurrence is independently either H or -O(CH3), R4 Each occurrence is (C 10 -C 20 ) alkyl, (C 10 -C 20 ) Alkenil, oh bi (C 10 -C 20 (Selected independently of Alkinnil) The present invention provides a composition comprising either or a pharmaceutically acceptable salt thereof.

[0023] This invention relates to one or more Streptococcus pneumoniae antigens and one or more of the following compounds: Also known as compound A-1 (N-(5-(4-(4-((5-amino-7-(butyl Mino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3,5-dimethyl Toxyphenyl)piperazin-1-yl)-5-oxopentyl) stearamide, Also known as compound A-2, (S)-N-(5-(4-(4-((5-amino-7-(( 1-Hydroxypentan-2-yl)amino)-2H-pyrazolo[4,3-d]pyrimid (-2-yl)methyl)-3,5-dimethoxyphenyl)piperazine-1-yl)-5- Oxopentyl stearamide, Also known as compound A-3, (S)-1-(4-(4-((5-amino-7-((1-H Droxypentan-2-yl)amino)-2H-pyrazolo[4,3-d]pyrimidine-2 -yl)methyl)-3,5-dimethoxyphenyl)piperazine-1-yl)octadecane -1-on, Also known as compound B-1, N-(5-(4-(4-((5-amino-7-(butylamine (no)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3-methoxyf (Piperadin-1-yl)-5-oxopentyl) stearamide, Also known as compound B-2, N-(5-(4-(4-((5-amino-7-(butylamine (no)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3-methoxyf (enyl)piperazine-1-yl)-5-oxopentyl)tetradecaneamide, Also known as compound B-3, N-(5-(4-(4-((5-amino-7-(butylamine (no)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3-methoxyf Enyl)piperazine-1-yl)-5-oxopentyl)oleamide, Also known as compound B-4, (9Z,12Z)-N-(5-(4-(4-((5-amino -7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl Octadeca (-3-methoxyphenyl)piperazin-1-yl)-5-oxopentyl)octadeca -9,12-dieneamide, Also known as compound B-5, N-(5-(4-(4-((5-amino-7-(butylamine (no)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3-methoxyf (enyl)-1,4-diazepan-1-yl)-5-oxopentyl) stearamide, Also known as compound B-6, N-(5-(4-(4-((5-amino-7-(butylamine (no)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3-methoxyf (Piperidin-1-yl)-5-oxopentyl) stearamide, Also known as compound B-7, N-(5-(3-(4-((5-amino-7-(butylamine (no)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3-methoxyf (Enyl)azetidine-1-yl)-5-oxopentyl)stearamide, Also known as compound B-8, 1-(4-((5-amino-7-(butylamino)-2H- Pyrazolo[4,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)-N -(3-stearamidopropyl)piperidine-4-carboxamide, Also known as compound B-9, (1s,3s)-3-(2-(4-(4-((5-amino- 7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl(methyl) -3-Methoxyphenyl)piperazin-1-yl)-2-oxoethyl)-N-octade Silcyclobutane-1-carboxamide, Also known as compound B-10, (1s,3s)-3-(2-(4-(4-((5-amino -7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl )-3-methoxyphenyl)piperazin-1-yl)-2-oxoethyl)-N-hexa Decylcyclobutane-1-carboxamide, Compound B-11, also known as N-(3-(4-(4-((5-amino-7-(butyl Mino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3-methoxy Phenyl)piperazin-1-yl)-3-oxopropyl)stearamide, Also known as compound B-12, N-(7-(4-(4-((5-amino-7-(butyl Mino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3-methoxy Phenyl)piperazin-1-yl)-7-oxoheptyl)stearamide, Also known as compound B-13, N-(3-(2-(4-(4-((5-amino-7-(B (Tylamino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3-methyl Toxyphenyl piperazine-1-yl-2-oxoethyl cyclobutyl stear Mido, Also known as compound B-14, N-(5-(4-(4-((5-amino-7-(butyl Mino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3-methoxy Phenyl)piperazin-1-yl)-4,4-dimethyl-5-oxopentyl) stear Mido, Also known as compound B-15, N-(6-(4-(4-((5-amino-7-(butyl Mino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3-methoxy Phenyl)piperazine-1-yl)-2-methyl-6-oxohexane-2-yl)ste Aramid, Compound B-16, also known as 1-(4-(4-((5-amino-7-(butylamino) -2H-pyrazolo[4,3-d]pyrimidine-2-yl(methyl)-3-methoxypheny (L)piperazine-1-yl)-5-(octadecyloxy)pentan-1-one, Compound B-17, also known as 1-(4-(4-((5-amino-7-(butylamino) -2H-pyrazolo[4,3-d]pyrimidine-2-yl(methyl)-3-methoxypheny (L)piperazine-1-yl)-5-(octadecylamino)pentan-1-one, Also known as compound B-18, N-(5-(4-(4-((5-amino-7-(butyl Mino)-3-methyl-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)- 3-Methoxyphenyl)piperazin-1-yl)-5-oxopentyl)stearamide, Also known as compound C-1, (9Z,12Z)-N-(4-((4-((5-amino-7 -(butylamino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl(methyl)- 3,5-Dimethoxybenzyl)(methyl)amino)butyl)octadeca-9,12-die Namido, Also known as compound C-2, N-(4-((4-((5-amino-7-(butylamino) -2H-pyrazolo[4,3-d]pyrimidine-2-yl(methyl)-3,5-dimethoxy Benzyl(methyl)amino(butyl)tetradecaneamide, Also known as compound C-3, N-(4-((4-((5-amino-7-(butylamino) -2H-pyrazolo[4,3-d]pyrimidine-2-yl(methyl)-3,5-dimethoxy Benzyl(methyl)amino(butyl)oleamide, Also known as compound C-4, N-(4-((4-((5-amino-7-(butylamino) -2H-pyrazolo[4,3-d]pyrimidine-2-yl(methyl)-3,5-dimethoxy Benzyl(methyl)amino(butyl)stearamide, Also known as compound C-5, N-(4-((4-((5-amino-7-(butylamino) -2H-pyrazolo[4,3-d]pyrimidine-2-yl(methyl)-3,5-dimethoxy Benzyl(methyl)amino(4-oxobutyl)stearamide, Compound D-1, also known as (6Z,9Z,28Z,31Z)-heptatriaconta-6 ,9,28,31-tetraen-19-yl(4-((4-((5-amino-7-(buty Luamino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3,5- Dimethoxybenzyl(methyl)amino(butyl)carbamate, Compound D-2, also known as 4-(4-((5-amino-7-(butylamino)-2H- Pyrazolo[4,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)-N -(3-stearamidopropyl)piperazine-1-carboxamide, 3-stearamidopropyl 4-(4-((5-amino-7- (Butylamino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3 -methoxyphenyl)piperazine-1-carboxylate, Also known as compound D-4, N-(5-(4-(4-((5-amino-7-(butylamine (no)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3-methoxyf (Piperadin-1-yl)-6,6,6-trifluorohexyl)stearamide, N-(4-((4-((7-(butylamino)-5-hydro, also known as compound D-5 Xy-2H-pyrazolo[4,3-d]pyrimidine-2-yl(methyl)-3,5-dimeth Xybenzyl(methyl)amino(butyl)stearamide, and Compound D-6, also known as (6Z,9Z,28Z,31Z)-heptatriaconta-6 ,9,28,31-tetraen-19-yl(5-(4-(4-((5-amino-7-( Butylamino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3- Methoxyphenyl)piperazine-1-yl)-5-oxopentyl)carbamate, The present invention provides a composition comprising either or a pharmaceutically acceptable salt thereof.

[0024] The present invention also comprises one or more Streptococcus pneumoniae antigens and a stable nanoemulsion. The product is a stable nanoemulsion, (i) formulas I, Ia, II, IIa, III, One or more compounds having the structure described in IIIa, IV, or IVa, or (if i) one or more of its pharmaceutically acceptable salts, ii) one or more emulsifiers, and iii) one A composition containing the above terpenes is provided.

[0025] The present invention also comprises one or more Streptococcus pneumoniae antigens and a stable nanoemulsion. The product is a stable nanoemulsion, (i) formulas I, Ia, II, IIa, III, One or more compounds having the structure described in IIIa, IV, or IVa, or (if i) one or more pharmaceutically acceptable salts thereof, ii) one or more sorbitan-based surfactants, (iii) Provide a composition comprising one or more terpenes.

[0026] The present invention also comprises one or more Streptococcus pneumoniae antigens and a stable nanoemulsion. The product is a stable nanoemulsion, (i) formulas I, Ia, II, IIa, III, Compounds having the structure described in IIIa, IV, or IVa, or pharmaceutically acceptable compounds thereof (ii) SPAN-85, (iii) PS-20 or PS-80, and (i v) Provide a composition containing squalene.

[0027] The present invention also comprises one or more Streptococcus pneumoniae antigens and a stable nanoemulsion. The product is a stable nanoemulsion, (i)N-(5-(4-(4-((5-Ammonia No-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)meth (L)-3-methoxyphenyl)piperazine-1-yl)-5-oxopentyl)stear (ii) Mid or a pharmaceutically acceptable salt thereof, (ii) SPAN-85, (iii) PS-20 Alternatively, the present invention provides a composition comprising PS-80 and (iv) squalene.

[0028] The present invention also includes (i) at least one Streptococcus pneumoniae. (Streptococcus pneumoniae) polysaccharide and (ii) ) Having the structure described in formulas I, Ia, II, IIa, III, IIIa, IV, or IVa (iii) a compound, or a pharmaceutically acceptable salt thereof, and (iv) SPAN-85 and (iv (v) PS-20 or PS-80, and (vi) squalene and a pharmaceutically acceptable carrier The present invention provides a pharmaceutical composition containing the body.

[0029] The present invention also includes (i) at least one Streptococcus pneumoniae. (Streptococcus pneumoniae) polysaccharide and (ii) )N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (i)-5-oxopentyl stearamide, or a pharmaceutically acceptable salt thereof, and (i ii) SPAN-85, (iv) PS-20 or PS-80, and (v) squalene (vi) a pharmaceutically acceptable carrier, and a pharmaceutical composition comprising these two elements is provided.

[0030] The present invention also relates to (i) at least one Streptococcus pneumoniae polysaccharide and (ii) formulas I, Ia, I Compounds having the structure described in I, IIa, III, IIIa, IV, or IVa, (iii) SPAN-85 and (iv) PS-20, and The immunotherapy includes PS-80, (v) squalene, and (vi) a pharmaceutically acceptable carrier. The present invention provides a composition for which the active ingredient is located.

[0031] The present invention also relates to (i) at least one Streptococcus pneumoniae polysaccharide and (ii) N-(5-(4 -(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrim Zin-2-yl)methyl)-3-methoxyphenyl)piperazin-1-yl)-5-oxy (iii) SPAN- 85, (iv) PS-20 or PS-80, (v) squalene, and (vi) pharmaceutical The present invention provides an immunogenic composition comprising a carrier that is acceptable to the present invention.

[0032] The present invention also relates to (i) at least one Streptococcus pneumoniae polysaccharide and (ii) formulas I, Ia, I Compounds having the structure described in I, IIa, III, IIIa, IV, or IVa, (iii) SPAN-85 and (iv) PS-20, and The invention provides a single-dose vaccine composition comprising PS-80, and the single dose of the vaccine composition is This is sufficient to induce the desired immune response against at least one Streptococcus pneumoniae polysaccharide. .

[0033] The present invention also relates to (i) at least one Streptococcus pneumoniae polysaccharide and (ii) N-(5-(4 -(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrim Zin-2-yl)methyl)-3-methoxyphenyl)piperazin-1-yl)-5-oxy (iii) SPAN- 85, (iv) PS-20 or PS-80, (v) squalene, and (vi) pharmaceutical A single-dose vaccine composition is provided, comprising a carrier that is acceptable to the vaccine composition. The amount is sufficient to induce the desired immune response against at least one Streptococcus pneumoniae polysaccharide. be.

[0034] The present invention also provides a method for treating or preventing pneumococcal disease in human patients, ( i) at least one Streptococcus pneumoniae polysaccharide and (ii) formulas I, Ia, II, IIa, III , compounds having the structure described in IIIa, IV, or IVa, or the pharmaceutically acceptable thereof. (iii) SPAN-85 and (iv) PS-20 or PS-80 and ( v) administer to the patient a pharmaceutical composition comprising squalene and (vi) a pharmaceutically acceptable carrier. To provide a method that includes doing so.

[0035] The present invention also provides a method for treating or preventing pneumococcal disease in human patients, ( i) at least one Streptococcus pneumoniae polysaccharide, and (ii) N-(5-(4-(4-((5- Mino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)me (Tyl)-3-methoxyphenyl)piperazine-1-yl)-5-oxopentyl)stear (iii) SPAN-85 and (iv) P (v) S-20 or PS-80, and (vi) a pharmaceutically acceptable carrier. The present invention provides a method comprising administering a pharmaceutical composition containing to a patient.

[0036] The present invention also includes (i) at least one Streptococcus pneumoniae polysaccharide carrier protein conjugate (ii) In formulas I, Ia, II, IIa, III, IIIa, IV or IVa A compound having the structure shown, or a pharmaceutically acceptable salt thereof, and (iii) SPAN-8 A pharmaceutical composition comprising (iv) PS-20 or PS-80 and (v) squalene. To provide.

[0037] The present invention also includes (i) at least one Streptococcus pneumoniae polysaccharide carrier protein conjugate (ii) In formulas I, Ia, II, IIa, III, IIIa, IV or IVa A compound having the structure shown, or a pharmaceutically acceptable salt thereof, and (iii) SPAN-8 5 and (iv) PS-20 or PS-80 and (v) squalene and (vi) pharmaceutically The present invention provides a pharmaceutical composition comprising an acceptable carrier.

[0038] The present invention also provides (i) a Streptococcus pneumoniae polysaccharide carrier protein conjugate, Each jugate is conjugated to a specific Streptococcus pneumoniae serotype of carrier protein. It contains polysaccharides, and the Streptococcus pneumoniae polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7 F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18 C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, c)1 , 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 3 5B, d)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 F, 24F, 33F, and 35B, e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, de-O-acetylation 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, Rabini f) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15C, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 It consists of a group of serotypes selected from F, 24F, 33F, and 35B, and is a carrier protein. This is CRM197, a Streptococcus pneumoniae polysaccharide carrier protein conjugate, and (ii) formula Having the structure described in I, Ia, II, IIa, III, IIIa, IV, or IVa (iii) a compound, or a pharmaceutically acceptable salt thereof, and (iv) SPAN-85 and P The present invention provides a pharmaceutical composition comprising S-20 or PS-80 and (v) squalene.

[0039] The present invention also provides (i) a Streptococcus pneumoniae polysaccharide carrier protein conjugate, Each jugate is conjugated to a specific Streptococcus pneumoniae serotype of carrier protein. It contains polysaccharides, and the Streptococcus pneumoniae polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7 F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18 C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, c)1 , 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 3 5B, d)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 F, 24F, 33F, and 35B, e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, de-O-acetylation 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, Rabini f) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15C, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 It consists of a group of serotypes selected from F, 24F, 33F, and 35B, and is a carrier protein. This is CRM197, a Streptococcus pneumoniae polysaccharide carrier protein conjugate, and (ii) formula Having the structure described in I, Ia, II, IIa, III, IIIa, IV, or IVa The compound, or a pharmaceutically acceptable salt thereof, and (iii) SPAN-85, (iv) PS -20 or PS-80, (v) squalene, and (vi) a pharmaceutically acceptable carrier. The present invention provides a pharmaceutical composition containing the following:

[0040] The present invention also provides (i) a Streptococcus pneumoniae polysaccharide carrier protein conjugate, Each jugate is conjugated to a specific Streptococcus pneumoniae serotype of carrier protein. It contains polysaccharides, and the Streptococcus pneumoniae polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7 F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18 C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, c)1 , 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 3 5B, d)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 F, 24F, 33F, and 35B, e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, de-O-acetylation 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, Rabini f) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15C, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 It consists of a group of serotypes selected from F, 24F, 33F, and 35B, and is a carrier protein. (ii)N -(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3 -d] Pyrimidine-2-yl)methyl)-3-methoxyphenyl)piperazine-1-yl (iii)-5-oxopentyl) stearamide, or a pharmaceutically acceptable salt thereof, and (iv) SPAN-85, (iv) PS-20 or PS-80, and (v) squalene. The present invention provides a pharmaceutical composition containing the following:

[0041] The present invention also provides (i) a Streptococcus pneumoniae polysaccharide carrier protein conjugate, Each jugate is conjugated to a specific Streptococcus pneumoniae serotype of carrier protein. It contains polysaccharides, and the Streptococcus pneumoniae polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7 F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18 C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, c)1 , 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 3 5B, d)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 F, 24F, 33F, and 35B, e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, de-O-acetylation 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, Rabini f) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15C, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 It consists of a group of serotypes selected from F, 24F, 33F, and 35B, and is a carrier protein. (ii)N -(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3 -d] Pyrimidine-2-yl)methyl)-3-methoxyphenyl)piperazine-1-yl (iii)-5-oxopentyl) stearamide, or a pharmaceutically acceptable salt thereof, and ) SPAN-85, (iv) PS-20 or PS-80, (v) Squalene, ( vi) To provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0042] The present invention also includes (i) at least one Streptococcus pneumoniae polysaccharide carrier protein conjugate (ii) In formulas I, Ia, II, IIa, III, IIIa, IV or IVa A compound having the structure shown, or a pharmaceutically acceptable salt thereof, and (iii) SPAN-8 an immunogenicity group including (iv) PS-20 or PS-80 and (v) squalene. To provide finished products.

[0043] The present invention also includes (i) at least one Streptococcus pneumoniae polysaccharide carrier protein conjugate (ii) In formulas I, Ia, II, IIa, III, IIIa, IV or IVa A compound having the structure shown, or a pharmaceutically acceptable salt thereof, and (iii) SPAN-8 5 and (iv) PS-20 or PS-80 and (v) squalene and (vi) pharmaceutically The present invention provides an immunogenic composition comprising an acceptable carrier.

[0044] The present invention also provides (i) a Streptococcus pneumoniae polysaccharide carrier protein conjugate, Each jugate is conjugated to a specific Streptococcus pneumoniae serotype of carrier protein. It contains polysaccharides, and the Streptococcus pneumoniae polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7 F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18 C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, c)1 , 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 3 5B, d)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 F, 24F, 33F, and 35B, e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, de-O-acetylation 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, Rabini f) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15C, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 It consists of a group of serotypes selected from F, 24F, 33F, and 35B, and is a carrier protein. This is CRM197, a Streptococcus pneumoniae polysaccharide carrier protein conjugate, and (ii) formula Having the structure described in I, Ia, II, IIa, III, IIIa, IV, or IVa (iii) a compound, or a pharmaceutically acceptable salt thereof, and (iv) SPAN-85 and P The present invention provides an immunogenic composition comprising S-20 or PS-80 and (v) squalene.

[0045] The present invention also provides (i) a Streptococcus pneumoniae polysaccharide carrier protein conjugate, Each jugate is conjugated to a specific Streptococcus pneumoniae serotype of carrier protein. It contains polysaccharides, and the Streptococcus pneumoniae polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7 F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18 C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, c)1 , 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 3 5B, d)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 F, 24F, 33F, and 35B, e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, de-O-acetylation 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, Rabini f) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15C, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 It consists of a group of serotypes selected from F, 24F, 33F, and 35B, and is a carrier protein. This is CRM197, a Streptococcus pneumoniae polysaccharide carrier protein conjugate, and (ii) formula Having the structure described in I, Ia, II, IIa, III, IIIa, IV, or IVa (iii) a compound, or a pharmaceutically acceptable salt thereof, and (iv) SPAN-85 and P (v) S-20 or PS-80, and (vi) a pharmaceutically acceptable carrier. The present invention provides an immunogenic composition containing ,

[0046] The present invention also provides (i) a Streptococcus pneumoniae polysaccharide carrier protein conjugate, Each jugate is conjugated to a specific Streptococcus pneumoniae serotype of carrier protein. It contains polysaccharides, and the Streptococcus pneumoniae polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7 F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18 C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, c)1 , 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 3 5B, d)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 F, 24F, 33F, and 35B, e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, de-O-acetylation 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, Rabini f) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15C, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 It consists of a group of serotypes selected from F, 24F, 33F, and 35B, and is a carrier protein. (ii)N -(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3 -d] Pyrimidine-2-yl)methyl)-3-methoxyphenyl)piperazine-1-yl (iii)-5-oxopentyl) stearamide, or a pharmaceutically acceptable salt thereof, and (iv) SPAN-85, (iv) PS-20 or PS-80, and (v) squalene. The present invention provides an immunogenic composition.

[0047] The present invention also provides (i) a Streptococcus pneumoniae polysaccharide carrier protein conjugate, Each jugate is conjugated to a specific Streptococcus pneumoniae serotype of carrier protein. It contains polysaccharides, and the Streptococcus pneumoniae polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7 F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18 C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, c)1 , 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 3 5B, d)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 F, 24F, 33F, and 35B, e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, de-O-acetylation 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, Rabini f) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15C, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 It consists of a group of serotypes selected from F, 24F, 33F, and 35B, and is a carrier protein. (ii)N -(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3 -d] Pyrimidine-2-yl)methyl)-3-methoxyphenyl)piperazine-1-yl (iii)-5-oxopentyl) stearamide, or a pharmaceutically acceptable salt thereof, and ) SPAN-85, (iv) PS-20 or PS-80, (v) Squalene, ( vi) To provide an immunogenic composition comprising a pharmaceutically acceptable carrier.

[0048] The present invention also includes (i) at least one Streptococcus pneumoniae polysaccharide carrier protein conjugate (ii) In formulas I, Ia, II, IIa, III, IIIa, IV or IVa A compound having the structure shown, or a pharmaceutically acceptable salt thereof, and (iii) SPAN-8 A single dose containing (iv) PS-20 or PS-80 and (v) squalene. The provided kuchin composition contains at least one polysaccharide carrier protein. It is sufficient to induce the desired immune response against the crystalline conjugate.

[0049] The present invention also includes (i) at least one Streptococcus pneumoniae polysaccharide carrier protein conjugate (ii) In formulas I, Ia, II, IIa, III, IIIa, IV or IVa A compound having the structure shown, or a pharmaceutically acceptable salt thereof, and (iii) SPAN-8 5 and (iv) PS-20 or PS-80 and (v) squalene and (vi) pharmaceutically The present invention provides a single-dose vaccine composition comprising an acceptable carrier.

[0050] The present invention also provides (i) a Streptococcus pneumoniae polysaccharide carrier protein conjugate, Each jugate is conjugated to a specific Streptococcus pneumoniae serotype of carrier protein. It contains polysaccharides, and the Streptococcus pneumoniae polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7 F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18 C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, c)1 , 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 3 5B, d)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 F, 24F, 33F, and 35B, e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, de-O-acetylation 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, Rabini f) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15C, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 It consists of a group of serotypes selected from F, 24F, 33F, and 35B, and is a carrier protein. This is CRM197, a Streptococcus pneumoniae polysaccharide carrier protein conjugate, and (ii) formula Having the structure described in I, Ia, II, IIa, III, IIIa, IV, or IVa (iii) a compound, or a pharmaceutically acceptable salt thereof, and (iv) SPAN-85 and P A single dose of the vaccine composition comprising S-20 or PS-80 and (v) squalene. However, it is not sufficient to induce the desired immune response against the polysaccharide carrier protein conjugate. The present invention provides a single-dose vaccine composition.

[0051] The present invention also provides (i) a Streptococcus pneumoniae polysaccharide carrier protein conjugate, Each jugate is conjugated to a specific Streptococcus pneumoniae serotype of carrier protein. It contains polysaccharides, and the Streptococcus pneumoniae polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7 F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18 C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, c)1 , 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 3 5B, d)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 F, 24F, 33F, and 35B, e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, de-O-acetylation 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, Rabini f) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15C, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 It consists of a group of serotypes selected from F, 24F, 33F, and 35B, and is a carrier protein. This is CRM197, a Streptococcus pneumoniae polysaccharide carrier protein conjugate, and (ii) formula Having the structure described in I, Ia, II, IIa, III, IIIa, IV, or IVa (iii) a compound, or a pharmaceutically acceptable salt thereof, and (iv) SPAN-85 and P (v) S-20 or PS-80, and (vi) a pharmaceutically acceptable carrier. The vaccine composition contains, and the single dose of the vaccine composition is such that the polysaccharide carrier protein conjugate is The present invention provides a single-dose vaccine composition that is sufficient to induce a desired immune response.

[0052] The present invention also provides (i) a Streptococcus pneumoniae polysaccharide carrier protein conjugate, Each jugate is conjugated to a specific Streptococcus pneumoniae serotype of carrier protein. It contains polysaccharides, and the Streptococcus pneumoniae polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7 F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18 C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, c)1 , 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 3 5B, d)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 F, 24F, 33F, and 35B, as well as e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 3 5B, and f)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 1 2F, 14, 15A, 15C, 16F, 18C, 19A, 19F, 22F, 23A, 23 It consists of a group of serotypes selected from B, 23F, 24F, 33F, and 35B, and the carrier The protein is CRM197, a Streptococcus pneumoniae polysaccharide carrier protein conjugate, ( ii) N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo [4,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine- 1-yl)-5-oxopentyl)stearamide, or a pharmaceutically acceptable salt thereof, (iii) SPAN-85, (iv) PS-20 or PS-80, and (v) Squalane The vaccine composition contains and, with a single dose, against the polysaccharide carrier protein conjugate. The present invention provides a single-dose vaccine composition that is sufficient to induce a desired immune response.

[0053] The present invention also provides (i) a Streptococcus pneumoniae polysaccharide carrier protein conjugate, Each jugate is conjugated to a specific Streptococcus pneumoniae serotype of carrier protein. It contains polysaccharides, and the Streptococcus pneumoniae polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7 F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18 C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, c)1 , 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 3 5B, d)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 F, 24F, 33F, and 35B, e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V , 10A, 11A, 12F, 14, 15A, de-O-acetylation 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, Rabini f) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 1 4, 15A, 15C, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23 It consists of a group of serotypes selected from F, 24F, 33F, and 35B, and is a carrier protein. (ii)N -(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3 -d] Pyrimidine-2-yl)methyl)-3-methoxyphenyl)piperazine-1-yl (iii)-5-oxopentyl) stearamide, or a pharmaceutically acceptable salt thereof, and ) SPAN-85, (iv) PS-20 or PS-80, (v) Squalene, ( vi) A pharmaceutically acceptable carrier, wherein the single dose of the vaccine composition is a polysaccharide carrier tan A single-dose vaccine sufficient to induce the desired immune response against protein conjugates. A tin composition is provided.

[0054] The present invention also provides a method for treating or preventing pneumococcal disease in human patients, ( i) at least one Streptococcus pneumoniae polysaccharide carrier protein conjugate, and (ii) formula I , having the structure described in Ia, II, IIa, III, IIIa, IV, or IVa (iii) SPAN-85 and (iv) PS Administering a pharmaceutical composition containing (v) squalene to a patient The present invention provides a method that includes the following:

[0055] The present invention also provides a method for treating or preventing pneumococcal disease in human patients, ( i) at least one Streptococcus pneumoniae polysaccharide carrier protein conjugate, and (ii) formula I , having the structure described in Ia, II, IIa, III, IIIa, IV, or IVa (iii) SPAN-85 and (iv) PS -20 or PS-80, (v) squalene, and (vi) a pharmaceutically acceptable carrier. The present invention provides a method comprising administering a pharmaceutical composition containing to a patient.

[0056] The present invention also provides a method for treating or preventing pneumococcal disease in human patients, ( i) A Streptococcus pneumoniae polysaccharide carrier protein conjugate, wherein each of the conjugates It contains a polysaccharide of a specific serotype of Streptococcus pneumoniae conjugated to a carrier protein, and pneumonia Streptococcal polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B, 23F, 2 4F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10 A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18C, 19A, 19F , 22F, 23B, 23F, 24F, 33F, and 35B, c) 1, 3, 4, 5, 6A , 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 18C, 1 9A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, d) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15B , 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F , and 35B, e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 16F, 18C, 19A, 19F, 2 2F, 23A, 23B, 23F, 24F, 33F, and 35B, as well as f)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C , 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F It consists of a group of serotypes selected from , and 35B, and the carrier protein is CRM197 (ii) Formulas I, Ia, II, I A compound having the structure described in Ia, III, IIIa, IV, or IVa, or the (iii) a pharmaceutically acceptable salt, (iii) SPAN-85, and (iv) PS-20 or PS A method comprising administering to a patient a pharmaceutical composition comprising (v) squalene and -80. provide.

[0057] The present invention also provides a method for treating or preventing pneumococcal disease in human patients, ( i) A Streptococcus pneumoniae polysaccharide carrier protein conjugate, wherein each of the conjugates It contains a polysaccharide of a specific serotype of Streptococcus pneumoniae conjugated to a carrier protein, and pneumonia Streptococcal polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B, 23F, 2 4F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10 A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18C, 19A, 19F , 22F, 23B, 23F, 24F, 33F, and 35B, c) 1, 3, 4, 5, 6A , 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 18C, 1 9A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, d) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15B , 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F , and 35B, e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 16F, 18C, 19A, 19F, 2 2F, 23A, 23B, 23F, 24F, 33F, and 35B, as well as f)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C , 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F It consists of a group of serotypes selected from , and 35B, and the carrier protein is CRM197 (ii) Formulas I, Ia, II, I A compound having the structure described in Ia, III, IIIa, IV, or IVa, or the (iii) a pharmaceutically acceptable salt, (iii) SPAN-85, and (iv) PS-20 or PS A pharmaceutical composition comprising (v) squalene and (vi) a pharmaceutically acceptable carrier. The present invention provides a method that includes administering a substance to a patient.

[0058] The present invention also provides a method for treating or preventing pneumococcal disease in human patients, ( i) A Streptococcus pneumoniae polysaccharide carrier protein conjugate, wherein each of the conjugates It contains a polysaccharide of a specific serotype of Streptococcus pneumoniae conjugated to a carrier protein, and pneumonia Streptococcal polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B, 23F, 2 4F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10 A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18C, 19A, 19F , 22F, 23B, 23F, 24F, 33F, and 35B, c) 1, 3, 4, 5, 6A , 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 18C, 1 9A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, d) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15B , 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F , and 35B, e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 16F, 18C, 19A, 19F, 2 2F, 23A, 23B, 23F, 24F, 33F, and 35B, as well as f)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C , 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F It consists of a group of serotypes selected from , and 35B, and the carrier protein is CRM197 (ii)N-(5-(4-(4 -((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidine- 2-Il)methyl)-3-methoxyphenyl)piperazine-1-yl)-5-oxopene (iii) Stearamide, or a pharmaceutically acceptable salt thereof, and SPAN-85 (iv) PS-20 or PS-80 and (v) squalene are used in a pharmaceutical composition for patients with (iv) PS-20 or PS-80 and (v) squalene. The present invention provides a method that includes administering the substance to a person.

[0059] The present invention also provides a method for treating or preventing pneumococcal disease in human patients, ( i) A Streptococcus pneumoniae polysaccharide carrier protein conjugate, wherein each of the conjugates It contains a polysaccharide of a specific serotype of Streptococcus pneumoniae conjugated to a carrier protein, and pneumonia Streptococcal polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B, 23F, 2 4F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10 A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18C, 19A, 19F , 22F, 23B, 23F, 24F, 33F, and 35B, c) 1, 3, 4, 5, 6A , 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 18C, 1 9A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, d) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15B , 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F , and 35B, e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 16F, 18C, 19A, 19F, 2 2F, 23A, 23B, 23F, 24F, 33F, and 35B, as well as f)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C , 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F It consists of a group of serotypes selected from , and 35B, and the carrier protein is CRM197 (ii)N-(5-(4-(4 -((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidine- 2-Il)methyl)-3-methoxyphenyl)piperazine-1-yl)-5-oxopene (iii) Stearamide, or a pharmaceutically acceptable salt thereof, and SPAN-85 (iv) PS-20 or PS-80, (v) squalene, and (vi) pharmaceutically acceptable The present invention provides a method comprising administering a pharmaceutical composition containing a carrier to a patient.

[0060] This invention also provides a method for preventing or reducing the likelihood of pneumococcal infection in human patients. The law includes (i) at least one Streptococcus pneumoniae polysaccharide carrier protein conjugate and (ii) The formulas I, Ia, II, IIa, III, IIIa, IV or IVa A compound having a structure, or a pharmaceutically acceptable salt thereof, and (iii) SPAN-85 (iv) PS-20 or PS-80 and (v) squalene are used in a pharmaceutical composition for patients with (iv) PS-20 or PS-80 and (v) squalene. The present invention provides a method that includes administering the substance to a person.

[0061] This invention also provides a method for preventing or reducing the likelihood of pneumococcal infection in human patients. The law includes (i) at least one Streptococcus pneumoniae polysaccharide carrier protein conjugate and (ii) The formulas I, Ia, II, IIa, III, IIIa, IV or IVa A compound having a structure, or a pharmaceutically acceptable salt thereof, and (iii) SPAN-85 (iv) PS-20 or PS-80, (v) squalene, and (vi) pharmaceutically acceptable The present invention provides a method comprising administering a pharmaceutical composition containing a carrier to a patient.

[0062] This invention also provides a method for preventing or reducing the likelihood of pneumococcal infection in human patients. The law is (i) a Streptococcus pneumoniae polysaccharide carrier protein conjugate, and Each gate contains multiple specific Streptococcus pneumoniae serotypes conjugated to a carrier protein. Contains sugars, and the Streptococcus pneumoniae polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 1 0A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23 B, 23F, 24F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, c)1, 3 , 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15 C, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B , d)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 1 0A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 16F, 18C, 19 A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, and f)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, It consists of a group of serotypes selected from 24F, 33F, and 35B, and the carrier protein is C RM197 is a Streptococcus pneumoniae polysaccharide carrier protein conjugate, and (ii) formula I, Compounds having the structure described in Ia, II, IIa, III, IIIa, IV, or IVa (iii) a substance, or a pharmaceutically acceptable salt thereof, and (iv) SPAN-85 and PS- Administering a pharmaceutical composition to a patient comprising (v) squalene and 20 or PS-80. This provides a method that includes [something].

[0063] This invention also provides a method for preventing or reducing the likelihood of pneumococcal infection in human patients. The law is (i) a Streptococcus pneumoniae polysaccharide carrier protein conjugate, and Each gate contains multiple specific Streptococcus pneumoniae serotypes conjugated to a carrier protein. Contains sugars, and the Streptococcus pneumoniae polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 1 0A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23 B, 23F, 24F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, c)1, 3 , 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15 C, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B , d)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 1 0A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 16F, 18C, 19 A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, and f)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, It consists of a group of serotypes selected from 24F, 33F, and 35B, and the carrier protein is C RM197 is a Streptococcus pneumoniae polysaccharide carrier protein conjugate, and (ii) formula I, Compounds having the structure described in Ia, II, IIa, III, IIIa, IV, or IVa (iii) a substance, or a pharmaceutically acceptable salt thereof, and (iv) SPAN-85 and PS- (v) squalene and (vi) a pharmaceutically acceptable carrier, The present invention provides a method comprising administering a pharmaceutical composition containing the above to a patient.

[0064] This invention also provides a method for preventing or reducing the likelihood of pneumococcal infection in human patients. The law is (i) a Streptococcus pneumoniae polysaccharide carrier protein conjugate, and Each gate contains multiple specific Streptococcus pneumoniae serotypes conjugated to a carrier protein. Contains sugars, and the Streptococcus pneumoniae polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 1 0A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23 B, 23F, 24F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, c)1, 3 , 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15 C, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B , d)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 1 0A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 16F, 18C, 19 A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, and f)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, It consists of a group of serotypes selected from 24F, 33F, and 35B, and the carrier protein is C RM197 is a Streptococcus pneumoniae polysaccharide carrier protein conjugate, and (ii)N-( 5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d ]Pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1-yl)- (iii)S 5-oxopentyl) stearamide, or a pharmaceutically acceptable salt thereof (iv) PS-20 or PS-80 and (v) squalene are included. The present invention provides a method comprising administering a pharmaceutical composition to a patient.

[0065] This invention also provides a method for preventing or reducing the likelihood of pneumococcal infection in human patients. The law is (i) a Streptococcus pneumoniae polysaccharide carrier protein conjugate, and Each gate contains multiple specific Streptococcus pneumoniae serotypes conjugated to a carrier protein. Contains sugars, and the Streptococcus pneumoniae polysaccharides are a) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 1 0A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23 B, 23F, 24F, 33F, and 35B, b) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B, c)1, 3 , 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15 C, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B , d)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, e) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 1 0A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 16F, 18C, 19 A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, and f)1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, It consists of a group of serotypes selected from 24F, 33F, and 35B, and the carrier protein is C RM197 is a Streptococcus pneumoniae polysaccharide carrier protein conjugate, and (ii)N-( 5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d ]Pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1-yl)- (iii)S 5-oxopentyl) stearamide, or a pharmaceutically acceptable salt thereof PAN-85, (iv) PS-20 or PS-80, (v) squalene, and (vi) A method is proposed, which involves administering to a patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier. To provide.

[0066] The above i) pharmaceutical composition, ii) immunogenic composition, and iii) single-dose vaccine composition In a specific embodiment of the substance, the composition contains more than 20 (20) different Streptococcus pneumoniae polysaccharides. The present invention includes a carrier protein conjugate. For example, the present invention includes (i) a carrier protein conjugate. Streptococcus pneumoniae polysaccharide carrier protein containing polysaccharides of specific serotypes of Streptococcus pneumoniae It is a polysaccharide conjugate selected from more than 20 (20) different Streptococcus pneumoniae polysaccharides. A group of serotypes of Streptococcus pneumoniae containing polysaccharides, including Streptococcus pneumoniae polysaccharide carrier proteins. A pharmaceutical composition containing jugate is provided.

[0067] In the specific embodiment described above, the serotype group is a) 1, 3, 4, 5, 6A, 6B, 7F , 8, 9V, 10A, 11A, 12F, 14, 15A, 15B, 16F, 18C, 19A , 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, or b )1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15 A, de-O-acetylated 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23 B, 23F, 24F, 33F, and 35B, or c) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 16F, 18C, 1 These are 9A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B. .

[0068] In the specific embodiment described above, the serotype group is a) 1, 3, 4, 5, 6A, 6B, 7F , 8, 9V, 10A, 11A, 12F, 14, 15A, 15B, 16F, 18C, 19A , 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, or b )1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15 A, de-O-acetylated 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23 B, 23F, 24F, 33F, and 35B, or c) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 16F, 18C, 1 These are 9A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B. The carrier protein is CRM197.

[0069] The above i) pharmaceutical composition, ii) immunogenic composition, and iii) single-dose vaccine composition In a specific embodiment of the substance, the composition contains more than 25 (25) different Streptococcus pneumoniae polysaccharides. The present invention includes a carrier protein conjugate. For example, the present invention includes (i) a carrier protein conjugate. Streptococcus pneumoniae polysaccharide carrier protein containing polysaccharides of specific serotypes of Streptococcus pneumoniae It is a polysaccharide conjugate selected from more than 25 (25) different Streptococcus pneumoniae polysaccharides. A group of serotypes of Streptococcus pneumoniae containing polysaccharides, including Streptococcus pneumoniae polysaccharide carrier proteins. A pharmaceutical composition containing jugate is provided.

[0070] In the specific embodiment described above, the serotype group is a) 1, 3, 4, 5, 6A, 6B, 7F , 8, 9V, 10A, 11A, 12F, 14, 15A, 15B, 16F, 18C, 19A , 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, or b )1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15 A, de-O-acetylated 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23 B, 23F, 24F, 33F, and 35B, or c) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 16F, 18C, 1 These are 9A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B. .

[0071] In the specific embodiment described above, the serotype group is a) 1, 3, 4, 5, 6A, 6B, 7F , 8, 9V, 10A, 11A, 12F, 14, 15A, 15B, 16F, 18C, 19A , 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B, or b )1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15 A, de-O-acetylated 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23 B, 23F, 24F, 33F, and 35B, or c) 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 16F, 18C, 1 These are 9A, 19F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B. The carrier protein is CRM197.

[0072] The above i) pharmaceutical composition, ii) immunogenic composition, and iii) single-dose vaccine composition In some embodiments of the material, the concentration of the compound ranges from 0.01 μg / mL to 1000 μg / mL. L or 0.1 μg / mL to 100 μg / mL or 80 μg / mL or 16 μg / mL It is L or 4 μg / mL.

[0073] The above i) pharmaceutical composition, ii) immunogenic composition, and iii) single-dose vaccine composition In some embodiments of the substance, the concentration of SPAN-85 is 0.001 mg / mL to 100 mg / mL or 0.01 mg / mL to 50 mg / mL or 0.1 mg / mL to 10 mg It is g / mL.

[0074] The above i) pharmaceutical composition, ii) immunogenic composition, and iii) single-dose vaccine composition In some embodiments of the substance, the concentration of PS-20 or PS-80 is 0.001 mg / mL~100 mg / mL or 0.01 mg / mL~50 mg / mL or 0.1 mg / The concentration is approximately 10 mg / mL.

[0075] The above i) pharmaceutical composition, ii) immunogenic composition, and iii) single-dose vaccine composition In some embodiments of the product, the concentration of squalene is 0.01 mg / mL to 100 mg / mL. mL or 0.02 mg / mL to 20 mg / mL or 1 mg / mL to 20 mg / mL be.

[0076] The above i) pharmaceutical composition, ii) immunogenic composition, and ii) single-dose vaccine composition In some embodiments, the concentration of the compound is 80 μg / mL, and SPAN-85 The concentration is 4.8 mg / mL, and the concentration of PS-20 or PS-80 is 4.8 mg / The volume is mL, and the squalene concentration is 16 mg / mL.

[0077] i) a pharmaceutical composition, ii) an immunogenic composition, and ii) the single-dose vaccine composition described above. , and iv) In some embodiments of the above single-dose vaccine composition, the concentration of the compound The concentration was 16 μg / mL, and the concentration of SPAN-85 was 4.8 mg / mL, and PS- The concentration of 20 or PS-80 is 4.8 mg / mL, and the concentration of squalene is 16 mg / mL. It is g / mL.

[0078] i) a pharmaceutical composition, ii) an immunogenic composition, and ii) the single-dose vaccine composition described above. , and iv) In some embodiments of the above single-dose vaccine composition, the concentration of the compound The concentration is 4 μg / mL, and the concentration of SPAN-85 is 4.8 mg / mL, and PS-2 The concentration of 0 or PS-80 is 4.8 mg / mL, and the concentration of squalene is 16 mg It is / mL.

[0079] The above i) pharmaceutical composition, ii) immunogenic composition, and iii) single-dose vaccine composition In some embodiments of the product, the composition further comprises L-met and EDTA.

[0080] Abbreviations and definitions The following abbreviations are used herein.

[0081] [Table 1] TIFF2026143520000018.tif230151TIFF2026143520000019.tif227136TIFF2026143520000020.tif204152

[0082] As used throughout this specification and the appended claims, the singular "one (a) "an" and "the" are used when the context clearly indicates otherwise. Unless otherwise specified, it includes multiple references.

[0083] Where used herein, the term "approximately" refers to the value as used herein. The same as the referenced value, or a value that is similar to the referenced value in the context. To refer to. Generally, a person skilled in the art familiar with the context will understand the difference encompassed by "about" in that context. You will understand the absolute quantity and / or relative degree of it. For example, in some embodiments So, the term "approximately" refers to 25%, 20%, 19%, 18%, 17%, and 16% of the reference value. , 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, It can include a range of values ​​of 4%, 3%, 2%, 1%, or less.

[0084] The term "adjuvant" as defined herein is used to enhance the immunogenicity of the compositions of the present invention. This refers to a useful compound, compound formulation, or composition. An adjuvant is i) administered alone. When this occurs, it enhances the immune response to antigens with weak immunogenicity (e.g., pneumococcal polysaccharide). For example, antibody titers that do not induce antibody titers or cell-mediated immune responses, or only weak antibody titers. ii) to induce a cell-mediated immune response, and / or iii) reducing the dose of antigen that is effective in achieving an immune response in the individual. It is possible to do so.

[0085] As used herein, the term “administration” refers to an active agent, composition, or formulation. This refers to the act of providing something to a target. Examples of routes of administration to the human body include the eyes (eye drops), mouth (oral), and skin. Skin (transdermal), nose (transnasal), lungs (inhalant), rectum, vagina, oral mucosa (cheek), ear, injection (for example) Depending on the location (intravenous (IV), subcutaneous, intratumoral, intraperitoneal, intramuscular (IM), intradermal (ID), etc.) It could be.

[0086] As used herein, “drug” refers to any chemical class of particles, compounds, molecules, and "Ta" refers to an actual entity.

[0087] As used herein, the term "alkyl" has a specified number of carbon atoms. This refers to straight-chain, cyclic, or branched saturated aliphatic hydrocarbons. The numerical range that indicates the total chain length is It can be given. For example, C1-C6 alkyl has a chain length of 1 to 6 atoms. The group may be the same or different, as defined below in this specification. They may be substituted with one or more "substituents". Unless otherwise indicated, alkyl groups are absent. It is a replacement.

[0088] As used herein, the term "alkenyl" refers to dienes, trienes, and A specified number of carbon atoms, including but not limited to tetraene unsaturated aliphatic hydrocarbons. It refers to a linear, cyclic, or branched unsaturated aliphatic hydrocarbon having a parent group. They may be the same or different, and one or more as defined below in this specification. They may be substituted with substituents. Unless otherwise specified, alkenyl groups are unsubstituted. ru.

[0089] As used herein, the term "alkynyl" refers to dienes, trienes, and A specified number of carbon atoms, including but not limited to tetraene unsaturated aliphatic hydrocarbons. It refers to a linear, cyclic, or branched unsaturated aliphatic hydrocarbon having a derivative. The alkynyl group is They may be the same or different, and one or more as defined below in this specification. They may be substituted with substituents. Unless otherwise specified, alkynyl groups are unsubstituted. ru.

[0090] As used herein, the term “antigen” means one or more substances that produce an immune response. It refers to any antigen that can be reacted to. Antigens are proteins, peptides, or polypeptides. To obtain. In certain embodiments, the antigen is a lipid or a carbohydrate. In this state, the antigen is a polysaccharide. In a particular embodiment, the antigen is pneumococcal polysaccharide. In certain embodiments, the polysaccharide is Streptococcus pneumoniae polysaccharide. The antigen is humoral and / or Alternatively, it may generate a CTL immune response.

[0091] As used herein, the term "aryl" refers to a group of carbon atoms comprising approximately 6 to approximately 14 carbon atoms. This refers to a carbocyclic aromatic monocyclic or bicyclic ring system. In one embodiment, the aryl group is approximately It contains 6 to approximately 10 carbon atoms. The aryl groups may be the same or different. It may be substituted with one or more "cyclic substituents" as defined below in the specification. Non-restrictive examples of aryl groups include phenyl and naphthyl. In this state, the aryl group is phenyl. Unless otherwise indicated, the aryl group is unsubstituted. be.

[0092] As used herein, the term “composition” means together with one or more additional components. Active pharmaceutical ingredients or biological components (e.g., Streptococcus pneumoniae polysaccharide carrier protein conjugate) This refers to a preparation containing (and compounds). The term "composition" is used in the context of "pharmaceutical composition". It is used interchangeably with "formulation". The composition is in liquid or solid (e.g., lyophilized). It is possible. Additional ingredients that may be included as needed include pharmaceutically acceptable excipients and additives. Additives, diluents, buffers, sugars, amino acids, chelating agents, surfactants, polyols, bulking agents, Stabilizers, cryoprotectants, solubilizers, emulsifiers, salts, adjuvants, isotonic agents, delivery vehicles, And antimicrobial preservatives are also mentioned. The composition is prepared according to the dosage and concentration used in the recipe. It is non-toxic to [the target group].

[0093] As used herein, the term "including" when used in conjunction with the compositions of the present invention The term may include any other ingredients such as adjuvants and excipients, or may be specifically listed. This refers to the addition of one or more polysaccharide-carrier protein conjugates that are not present in the original text.

[0094] When used herein, polyhydric polysaccharide mixtures or polyhydric polysaccharide carrier protein conjugates When used with a mixture, "consisting of" The terminology and variations such as "consist of" are specific to those pneumonia cases. They possess a chainococcal polysaccharide or Streptococcus pneumoniae polysaccharide carrier protein conjugate and are of different serotypes. Other Streptococcus pneumoniae polysaccharides or Streptococcus pneumoniae polysaccharide carrier protein conjugates derived from This refers to a mixture that does not contain [a specific compound].

[0095] As used herein, "consists essent The terms "easily of" and "essentially consisting of" "(es)" or "essentially consisting of" Variations such as "(sentially of)" indicate the inclusion of any enumerated element or group of elements. , and indicate and specify any inclusion of other elements of similar or different nature to the enumerated elements. The basic or novel properties of the administered regimen, method, or composition are not substantially altered. stomach.

[0096] As used herein, "de-o-acetylated-15B" or "de-o-acetylated- The terms "15B" or "de-O-Ac-15B" refer to the repeated single O-acetyl content. This refers to deoxyacetylated serotype 15B that is less than 10% per O-position. In another embodiment, O -The acetyl content is less than 5% per repeating unit. In another embodiment, O-acetyl The chill content is less than approximately 1% per repeating unit. In another embodiment, O-acetyl The content is less than 1% per repeating unit. In another embodiment, the O-acetyl content The O-acetyl content is less than 0.5% per repeating unit. In another embodiment, the O-acetyl content is , less than 0.1% per repeating unit. In another embodiment, the O-acetyl content is The repeat rate is 0% per unit. The de-O-acetylation process is, for example, Rajam et al.,Clinical and Vaccine Immunology,2 As described in 007,14(9):1223-1227, it is known in the art that be.

[0097] As used herein, the term “dosage” refers to the amount taken at a particular time or Drugs, APIs (active pharmaceutical ingredients), formulations, compositions, and pharmaceutical compositions that are recommended for ingestion. This refers to the quantity of a substance or immunogenic composition.

[0098] As used herein, the term "heteroaryl" refers to a group of approximately 5 to 14 heteroaryl rings. This refers to an aromatic monocyclic or polycyclic ring system containing atoms, where 1 to 4 ring atoms are independently O, N, Or it is S, and the remaining ring atoms are carbon atoms. In one embodiment, a heteroaryl group It has 5 to 10 ring atoms. In another embodiment, the heteroaryl group is monocyclic. In another embodiment, the heteroaryl group has five or six ring atoms. The heteroaryl groups may be the same or different, and are defined below in this specification. It may be substituted by one or more "ring substituents" as defined. The Riehl group is linked via ring carbon atoms, and any nitrogen atom of the heteroaryl group corresponds to It may be oxidized to an N-oxide. In one embodiment, the heteroaryl group is a 5-membered heteroaryl group. It is a teloaryl. In another embodiment, the heteroaryl group is a 6-membered heteroaryl. In another embodiment, the heteroaryl group is a 5-6 member heteroaryl group fused to a benzene ring. Contains heteroaryl groups. Unless otherwise indicated, heteroaryl groups are unsubstituted.

[0099] As used herein, the term "heterocycloalkyl" refers to 3 to about 11 It contains a ring atom and contains at least one ring heteroatom selected from N, S, and O. The remaining ring atoms are carbon atoms, saturated or partially unsaturated non-aromatic monocyclic and bicyclic compounds. (Including spirocyclic rings), or bridged carbocyclic rings or ring systems. Heterocycloid Unless otherwise specified, lukyl groups can be bonded via ring carbon or ring nitrogen atoms. The heterocycloalkyl ring is located on the ring carbon and / or (one or more) ring nitrogen atoms. It can be substituted. In one embodiment, the heterocycloalkyl group is monocyclic and has about 3 to about 7 It has two ring atoms. In another embodiment, the heterocycloalkyl group is monocyclic and about It has 4 to about 7 ring atoms. In other embodiments, the heterocycloalkyl group is bicyclic Yes, it has 7-10 ring atoms, 8-10 ring atoms, or 9 or 10 ring atoms. In yet another embodiment, the heterocycloalkyl group is monocyclic and has five or It has six ring atoms. In one embodiment, the heterocycloalkyl group is monocyclic. In this embodiment, the heterocycloalkyl group is bicyclic. , may be substituted. In some embodiments, the heterocycloalkyl group has nitrogen, sulfur in the ring. It has one or two heteroatoms selected from yellow and oxygen atoms. In some embodiments, A heterocycloalkyl group is a ring containing one atom selected from nitrogen, sulfur, and oxygen atoms. It has heteroatoms. In some embodiments, the heteroatoms are O, S, S(O), S( Selected from O)2 and -NH-, -N(alkyl)-. A non-limiting example is E ethyl, thioether, amine, hydroxymethyl, 3-hydroxypropyl, 1,2- Dihydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-dimethylaminoethyl Examples include aliphatic groups containing heteroatoms, such as 'L'.

[0100] As used herein, the terms “immunogenic” or “immunogenic” refer to antigens ( For example, it refers to the ability of a substance (such as pneumoniae-streptococcal polysaccharide) to trigger an immune response in a target. The term "composition" applies to drugs, APIs, formulations, compositions, or pharmaceutical compositions. It refers to the ability to trigger an immune response.

[0101] As used herein, the phrase “patients or subjects requiring treatment” means “pneumonia.” Individuals who have been previously exposed to or infected with streptococcal polysaccharides, or who have previously received a vaccine against streptococcal polysaccharides. Those who have been vaccinated, as well as those who are susceptible to infection, or for whom a reduction in the possibility of infection is desired. This includes any person, such as an immune-deficient person, an elderly person, a child, an adult, or a healthy individual. .

[0102] As used herein, the phrase "suitable for the prevention of pneumococcal disease" means "vaccine The ointment or composition is used for general pneumococcal disease, invasive pneumococcal disease (IPD), and pneumococcal pneumonia. (PP), pneumococcal meningitis, pneumococcal bacteremia, caused by Streptococcus pneumoniae This includes, but is not limited to, invasive diseases and otitis media caused by Streptococcus pneumoniae. To prevent one or more diseases caused by any serotype of Streptococcus pneumoniae that are not treated Therefore, it means that it has been approved by one or more regulatory authorities, such as the U.S. Food and Drug Administration. ru.

[0103] As used herein, the term “multiple doses” means inducing a sustained immune response. to provide protection from disease, or to reduce the likelihood of infection by infectious agents. Therefore, in clinical regimens, administration or injection of more than one dose or component thereof is prohibited. This refers to the required vaccine composition, or pharmaceutical composition, or immunogenic composition. Those skilled in the art will know. For example, by measuring antibody titers over a specified period, a persistent immune response can be detected. You will understand how to make that decision.

[0104] As used herein, “patient” (or, as used herein, “subject”) ) refers to mammals that may be infected with pneumonia streptococcal polysaccharide. In a preferred embodiment, The patient is a human being. The patient can be treated prophylactically or therapeutically. Prophylactic treatment is , reducing the likelihood, severity, or impact of pneumococcal infection, such as pneumococcal pneumonia. It provides sufficient protective immunity to allow the disease to progress. Therapeutic treatment reduces the severity of pneumococcal infections. It can be administered to induce a bowel movement or to prevent recurrence or its clinical effects. Preventive treatment involves the pneumococcal conjugate composition of the present invention as described herein or This can be carried out using kutin or an immunogenic composition. The present invention involves the use of pneumococcal control The jugate composition or vaccine, or immunogenic composition, is intended for use in the general population or in patients with pneumonia. People at high risk of cocci infection, such as the elderly, or those living with or caring for the elderly. It can be administered to those who care for the person.

[0105] As used herein, the term "PCV1" refers to a conjugate of a carrier protein. A single Streptococcus pneumoniae polysaccharide carrier containing a capsular polysaccharide derived from a Streptococcus pneumoniae serotype. This refers to a monovalent pneumococcal conjugate vaccine or composition containing a protein conjugate. In a specific embodiment, the carrier protein is CRM197.

[0106] As used herein, the term "PCV24" refers to 23 Streptococcus pneumoniae polysaccharides. A 24-valent pneumococcal conjugate vaccine or composition containing a carrier protein conjugate Each capsule, derived from a Streptococcus pneumoniae serotype, is conjugated to a carrier protein. It contains polysaccharides, and the serotypes of Streptococcus pneumoniae are 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V. 10A, 11A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23B, 2 Serotypes 4F, 31, 33F, and 35B, as well as the following serotypes: 15B, 15 At least one of C, or de-O-acetylated -15B. In certain embodiments The serotypes of serotype 15 are serotype 15C or de-O-acetylated 15B. In terms of application, serotype 15 is serotype de-O-acetylated 15B. Specific implementation Morphologically, it consists of one or more carrier proteins from the Streptococcus pneumoniae polysaccharide carrier protein conjugate. The protein is CRM197. In a further embodiment, the Streptococcus pneumoniae polysaccharide carrier protein Each of the protein conjugates is CRM197.

[0107] As used herein, the term "PCV26" refers to 25 Streptococcus pneumoniae polysaccharides. 26-valent pneumococcal conjugate vaccine or composition containing carrier protein conjugate Each capsule, derived from a Streptococcus pneumoniae serotype, is conjugated to a carrier protein. It contains polysaccharides, and the serotypes of Streptococcus pneumoniae are 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V. 10A, 11A, 12F, 14, 15A, 16F, 18C, 19A, 19F, 22F, 2 Serums of serotypes 3A, 23B, 24F, 31, 33F, and 35B, as well as the following 15 serotypes Type: At least one of 15B, 15C, or de-O-acetylated-15B. In certain embodiments, the serotype of serotype 15 is serotype 15C or de-O-acetylated 15 It is B. In another embodiment, serotype 15 is serotype de-O-acetylated 15B. In a specific embodiment, one of the Streptococcus pneumoniae polysaccharide carrier protein conjugates One or more carrier proteins are CRM197. In further embodiments, Streptococcus pneumoniae Each of the carrier proteins in the polysaccharide carrier protein conjugate is CRM197.

[0108] When used herein, the term "pharmaceutical" is used with respect to carriers, diluents, or excipients of pharmaceutical compositions. The term "generally acceptable" means that the carrier, diluent, or excipient interacts with other components of the composition. It must be suitable and must not be harmful to its recipient.

[0109] As used herein, the term “pharmaceutical composition” means a combination of one or more additional components. in addition, compositions containing active pharmaceutical or biological components, for example, one or more active agents This refers to a composition formulated with a pharmaceutically acceptable carrier. In addition, the terms "pharmaceutical preparation" and "preparation" are used interchangeably with "pharmaceutical composition." In some embodiments, the active agent exerts a predetermined therapeutic effect when administered to the relevant population. It is present in a unit dose appropriate for administration in a treatment regimen that shows a statistically significant probability of achieving the desired result. The pharmaceutical composition or preparation may be a liquid or a solid (e.g., lyophilized). Depending on the circumstances, additional ingredients that may be included include pharmaceutically acceptable excipients, additives, diluents, Buffering agents, sugars, amino acids, chelating agents, surfactants, polyols, bulking agents, stabilizers, freeze-drying agents Protective agents, solubilizers, emulsifiers, salts, adjuvants, isotonic agents, delivery vehicles, and antimicrobial protection agents. Examples include preservatives. Pharmaceutical compositions or preparations are prepared according to the dosage and concentration used in the recipe. It is nontoxic to the toxic agent. In some embodiments, the pharmaceutical composition conforms to the following: It can be specially formulated for administration in solid or liquid form, including: oral administration For example, oral medications (aqueous or non-aqueous solutions or suspensions), tablets, for example, buccal, sublingual, And formulations targeting systemic absorption, including boluses, powders, granules, and pastes for application to the tongue. T; Parenteral administration, for example by subcutaneous, intramuscular, intravenous, or epidural injection, for example, sterile Solutions or suspensions, or sustained-release formulations; suitable for topical application, e.g., skin, lungs, or oral cavity. Topical application as a cream, ointment, or controlled-release patch or spray; vagina Internally or rectally, for example, as a pessary, cream, or foam; sublingually; orally; transdermally Cutaneous; or transnasal, transpulmonary, and other mucosal surfaces. In some embodiments, The term "agent" refers to a single dose of vaccine that can be contained in any volume suitable for injection. vinegar.

[0110] As used herein, the term "pneumococcal conjugate" or "pneumococcal polysaccharide carrier" is used. The term "protein conjugate" refers to the polysaccharide carrier protein conjugate of Streptococcus pneumoniae. It refers to the word "to".

[0111] When used herein, the term "pneumococcal conjugate vaccine" (or "PCV") is used. The term refers to a disease caused by one or more serotypes of Streptococcus pneumoniae. or (one or more) pneumococcal polysaccharide carrier proteins that provide active immunity to a pathological condition It is a pharmaceutical preparation or composition containing a quality conjugate.

[0112] As used herein, the term “cyclic substituent” means, for example, available on the cyclic system This refers to substituents attached to aromatic or non-aromatic ring systems that replace hydrogen atoms. They may be the same or different, and each can be selected independently. An example of a ring substituent is A Lukyl, alkenyl, alkynyl, aryl, heteroaryl, -OH, hydroxyal Kill, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl -O-aryl, -O-alkylene-aryl, acyl, -C(O)-aryl, ha -NO2, -CN, -SF5, -C(O)OH, -C(O)O-alkyl, -C(O )O-aryl, -C(O)O-alkylene-aryl, -S(O)-alkyl, -S( O)2-alkyl, -S(O)-aryl, -S(O)2-aryl, -S(O)-hete loaryl, -S(O)2-heteroaryl, -S-alkyl, -S-aryl, -S- Heteroaryl, -S-alkylene-aryl, -S-alkylene-heteroaryl, - S(O)2-alkylene-aryl, -S(O)2-alkylene-heteroaryl, cy Roalkyl, heterocycloalkyl, -OC(O)-alkyl, -OC(O)-ali Examples include -OC(O)-cycloalkyl compounds. Further examples of cyclic substituents are For example, (C1-C4) alkyl, (C1-C4) alkenyl, (C1-C4) alkini -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1 -C4) Examples include alkynyl, chlorine, and fluorine.

[0113] As used herein, the term “single dose” means a dose that induces a sustained immune response. A single dose in a clinical regimen to provide protection from disease (e.g., pneumococcal disease). Or it refers to a vaccine composition that requires only injection. Those skilled in the art will know, for example, for a specified period Understanding how to determine a persistent immune response by measuring antibody titers over time. It is likely.

[0114] As used herein, “substituent” or “any substituent” or “substituted” The phrase "may" means, for example, an alkyl group that replaces an available hydrogen on the group, This refers to an alkenyl group or a substituent bonded to an alkynyl group. The substituents are the same. They may also be different and each can be selected independently. Examples of substituents include alkyl and aldehyde. Kenyl, Alkinyl, Aryl, Heteroaryl, -OH, Hydroxyalkyl, Halo Lukil, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-a Reel, -O-alkylene-aryl, acyl, -C(O)-aryl, halo, -NO2 -CN, -SF5, -C(O)OH, -C(O)O-alkyl, -C(O)O-alkyl -C(O)O-alkylene-aryl, -S(O)-alkyl, -S(O)2-alkyl Kill, -S(O)-aryl, -S(O)2-aryl, -S(O)-heteroaryl, -S(O)2-heteroaryl, -S-alkyl, -S-aryl, -S-heteroaryl -S-alkylene-aryl, -S-alkylene-heteroaryl, -S(O)2- Alkylene-aryl, -S(O)2-alkylene-heteroaryl, cycloalkyl, Heterocycloalkyl, -OC(O)-alkyl, -OC(O)-aryl, and -OC(O)-cycloalkyl is one example. Further examples of substituents include (C1- C4) alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, -OH, -O (C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkini Examples include fluorine, chlorine, and fluorine.

[0115] As used herein, “SNE” or “stable nanoemulsion” refers to formulas I, Ia, Compounds of type II, IIa, III, IIIa, IV, or IVa, or their pharmaceutically acceptable compounds. This refers to a composition containing a salt that is contained. In some embodiments, SNE is a salt of formula I, Ia, II , compounds of type IIa, III, IIIa, IV or IVa, or their pharmaceutically acceptable Salt, sorbitan trioleate (SPAN-85), and polysorbate-20 (P The composition includes S-20) or polysorbate-80 (PS-80), squalene, and The substance is in the form of a nanoemulsion. In some embodiments, SNE is expressed by formulas I, Ia, Compounds of type II, IIa, III, IIIa, IV, or IVa, or their pharmaceutically acceptable compounds. It contains salts, SPAN-85, PS-20, and squalene, and several fruits In terms of administration methods, SNE is SPAN-85 with a concentration of 0.001 mg / mL to 10 mg / mL, and 0 PS-20 with a concentration of 0.001 mg / mL to 10 mg / mL, and 0.01 mg / mL to 100 mg It contains squalene at a concentration of / mL. In further embodiments, SNE is 0.05 mg / mL SPAN-85 is ~5 mg / mL, and PS-20 is 0.05 mg / mL to 5 mg / mL. , comprising squalene in a concentration of 0.05 mg / mL to 50 mg / mL. Further embodiments So, SNE is SPAN-85 with a concentration of 0.1 mg / mL to 1 mg / mL, and 0.1 mg / mL It contains PS-20 at L~1 mg / mL and squalene at 1 mg / mL~10 mg / mL. When used herein, SNE is used interchangeably with "squalene emulsion". It will be done.

[0116] Nanoemulsions, also known as nanometer-sized emulsions, are two types of It is an immiscible fine oil-in-water (o / w) dispersion. Nanoemulsions are used to carry drug molecules. It is a system of colloidal particles in the submicron size range that acts as a body. Their sizes are The wavelength varies from 10 to 1,000 nm. These supports are solid spheres, and their surfaces are amorphous. It is lipophilic in nature.

[0117] As used herein, the term “therapeutic dose” means a dose obtained in humans or animals. A sufficient amount of active components (antigens) to produce the desired therapeutic effect, for example, to induce an immune response. to treat, cure, prevent or inhibit the onset and progression of a disease or its symptoms. The amount necessary to improve symptoms or cause disease regression. This refers to the required amount. The therapeutically effective dose is determined by the structure and potency of the active components and the intended dosage. It may vary depending on the form. A person skilled in the art can determine the therapeutically effective amount of a given active component in a vaccine. It can be easily determined.

[0118] As used herein, the term “valence” means a specified number of polysaccharides in a composition or This refers to the presence of a polysaccharide-carrier protein conjugate.

[0119] As used herein, the terms “vaccine” or “vaccine composition” mean “anti- This refers to biological agents used to stimulate the body's production and provide immunity against infections. .

[0120] As used herein, the term "carbon or nitrogen bonded spacer" means carbon (- This refers to any chemical combination in which C) or nitrogen (-N) is linked to the benzyl group of the formula of the present invention (Formula I (See the bond of variable "A" in Ia). Examples of carbon or nitrogen bond spacers are C1-C6. Alkyl, heterocycloalkyl, aryl, and heteroaryl, the alkyl The aryl, heterocycloalkyl, aryl, and heteroaryl elements may be substituted.

[0121] Unless otherwise specified, when a linker is described throughout this disclosure, the linker base is the first The available bond of 1 is attached to the left of the portion of the compound adjacent to the linker group, and the linker group Terminally available bonds are attached to the right-hand terminal portion of the compound adjacent to the linker group. If the linker (L) is -CH2-CF2-, then the definition of L is A-CH2-CF2- It contains only B, and does not contain A-CF2-CH2-B.

[0122] As used herein, the term “functional group” refers to a carbon or nitrogen bond spacer. This refers to any chemical properties that can be linked to a lipid group. Examples of functional groups are: [ka] The equation is such that n is 0, 1, 2, 3, 4, or 5.

[0123] Further examples of functional groups are: [ka] That is the case.

[0124] As used herein, the term "lipid" refers to a substance that is insoluble in water but soluble in organic solvents. refers to any chemical property that is soluble. Examples of lipids are represented by variable D (see Formula I and Formula Ia) , which is selected from (C6-C 20 )alkyl, (C6-C 20 )alkenyl, and (C6- C 20 )alkynyl, wherein said alkyl, alkenyl and alkynyl may optionally be substituted.

[0125] A further example of a lipid is

Chemical Formula

Chemical Formula

[0126] A further example of a lipid is represented by variable D (see Formula I and Formula Ia), wherein D is

Chemical Formula

[0127] The compounds of the present invention having one or more chiral centers are stereoisomers unless otherwise specified. They exist as compounds or substantially pure individual diastereomers or enantiomers. The present invention relates to formulas I, Ia, II, IIa, III, IIIa, IV, and IVa. This includes all stereoisomers of the compound. Unless otherwise specified, this description is based on the stereochemistry of the compound. This means that all such isomers of these compounds are included. Formulas I, Ia, The chiral centers present in compounds II, IIa, III, IIIa, IV, and IVa are All can independently have either an (R) configuration or an (S) configuration. Chiral carbon When the bond to the element is shown as a straight line in the structural formula of the present invention, the (R) of the chiral carbon and (S) Both configurations, and therefore both enantiomers and mixtures thereof, are included in the formula. It is understood that the compound names are listed without specifying the chiral carbon. If present, both the (R) and (S) configurations of the chiral carbon, and therefore the individual enant It is understood that omers, diastereomers, and mixtures thereof are included in the name. The production of specific stereoisomers or mixtures thereof is the process of producing such stereoisomers or mixtures. Although the substance may be identified in the examples in which it was obtained, this does not mean all stereoisomers and The inclusion of such mixtures is not limited to the scope of the present invention.

[0128] Any component or formula I, Ia, II, IIa, III, IIIa, IV, and I In Va, if any variable (e.g., n, Rb, etc.) appears two or more times, then each occurrence That definition is independent of the definition in all other occurrences. Also, substituents and / or The combination of variables is only permissible if such a combination results in a stable compound. It will be done.

[0129] "Stable" compounds can be prepared and isolated, and their structure and properties remain intact. or for a period sufficient to allow the use of the compound for the purposes described herein (e.g., (Use as an adjuvant in immunogenic compositions administered to the target), essentially altered These are compounds that can be left as they are. The compounds of the present invention are of formulas I, Ia, II, and II. This is limited to stable compounds included in a, III, IIIa, IV, and IVa.

[0130] The dashed lines used in this specification [ka] The lines indicate the bonding points with the rest of the compound. Lines drawn on the ring system, for example: [ka] This indicates that the bond can be attached to any of the replaceable ring atoms.

[0131] compound The compounds described herein are the pneumococcal compositions or pneumococcal conjugates described herein. Gate composition or pneumococcal vaccine (PV) or pneumococcal conjugate vaccine ( This invention is useful for adjuvant formulations that are useful for boosting the immunological response of PCV. ru.

[0132] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes: [ka] (In the formula, R a H, -OH, (C1-C6)alkyl, (C1-C6)alkenyl, (C1- C6) Alkynyl, -O(C1-C6) alkyl, -O(C1-C6) alkenyl, -O (C1-C6) Selected from alkynyl, chlorine, fluorine, and -NR'R'', the above ( C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, -O( C1-C6) alkyl, -O(C1-C6) alkenyl, and -O(C1-C6) Quinyl is -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O (C1-C4) 1 to independently selected from the group consisting of alkynyl, chlorine, and fluorine It may also be substituted with four substituents. R a’ is H, -OH, (C1-C6)alkyl, (C1-C6)alkenyl, (C1 -C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C6)alkenyl, - Selected from O(C1-C6)alkynyl, chlorine, fluorine, and -NR'R'', (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O (C1-C6)alkyl, -O(C1-C6)alkenyl, and -O(C1-C6) Lukinyl is -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, - One independently selected from the group consisting of O(C1-C4)alkynyl, chlorine, and fluorine. It may also be substituted with up to 4 substituents. R a’’ H, -OH, (C1-C6)alkyl, (C1-C6)alkenyl, (C 1-C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C6)alkenyl, Selected from -O(C1-C6)alkynyl, chlorine, fluorine, and -NR'R'', prior Note (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, - O(C1-C6) alkyl, -O(C1-C6) alkenyl, and -O(C1-C6) Alkinyls are -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, Independently selected from the group consisting of -O(C1-C4)alkynyl, chlorine, and fluorine. It may be substituted with 1 to 4 substituents. R' and R'' are H, (C1-C6) alkyl, (C1-C6) alkenyl, and A (C1-C6) alkyl, (C) is independently selected from (C1-C6)alkynyl. (C1-C6) alkenyls and (C1-C6) alkynyls are -OH, -O(C1-C4 )alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, It may also be substituted with 1 to 4 substituents independently selected from the group consisting of fluorine. , or R' and R'', together with the nitrogen they are bound to, bind together. (C3-C6) heterocycloalkyl is formed, and the (C3-C6) heterocycloalkyl Kill is -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O( C1-C4) 1-4 independently selected from the group consisting of alkynyl, chlorine, and fluorine. It may be substituted with one substituent, R b Each appearance is H, -OH, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C6)alkene Independently selected from -O(C1-C6)alkynyl, chlorine, fluorine, or NR'R'' is selected, said (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) al kynyl, -O(C1-C6) alkyl, -O(C1-C6) alkenyl, and -O(C 1-C6) alkynyl is independently from the group consisting of -OH, -O(C1-C4) alkyl, -O(C1-C4) a lkenyl, -O(C1-C4) alkynyl, chlorine, and fluorine may be substituted with 1 to 4 selected substituents, A is (C1-C6) alkyl, heterocycloalkyl, heterocycloalkyl-C( O)-R z -, (C1-C4) alkyl-N(R z )-R z -, aryl, and hetero a carbon or nitrogen-bonded spacer selected from aryl, wherein said (C1-C6) alky l, heterocycloalkyl, aryl, and heteroaryl are -OH, (C1-C6 ) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, -O(C1-C6 ) alkyl, -O(C1-C6) alkenyl, -O(C1-C6) alkynyl, chlorine, flu orine, and NR'R'' are substituted with 1 to 6 substituents independently selected from the group consisting of and may be optionally substituted, wherein said (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C 6) alkynyl, -O(C1-C6) alkyl, -O(C1-C6) alkenyl, and -O(C1-C6) alkynyl is -OH, -O(C1-C4) alkyl, -O(C1- C4) alkenyl, -O(C1-C4) alkynyl, chlorine, and fluorine are selected from the group consisting of may be substituted with 1 to 6 independently selected substituents, R z each occurrence of is independently H or (C1-C6) alkyl, B is

Chemical Formula

[0133] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where m is 0, 1, 2, 3, 4 or 5 That is the case.

[0134] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where m is 0, 1, 2, 3, or 4. be.

[0135] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and the formula where m is 0, 1, 2, or 3. .

[0136] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound is represented by the structure described, and includes, where m is 0, 1, or 2.

[0137] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound is represented by the structure shown, and includes, where m is 2.

[0138] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound is represented by the structure shown, and includes, where m is 1.

[0139] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound is represented by the structure shown, and includes, where m is 0.

[0140] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where n is 0, 1, 2, 3, 4, or The answer is 5.

[0141] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where n is 0, 1, 2, 3, or 4. be.

[0142] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and the compound comprising, where n is 0, 1, 2, or 3. .

[0143] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound is represented by the structure described, and includes, where n is 0, 1, or 2.

[0144] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound is represented by the structure shown, and includes, where n is 2.

[0145] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound is represented by the structure shown, and includes, where n is 1.

[0146] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound is represented by the structure shown, and includes, where n is 0.

[0147] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and, wherein the formula, R' and R'' are independently, H, (C1-C6) alkyl, (C1-C6) alkenyl, or (C1-C6) alkyl It is a nyl, and the (C1-C6) alkyl, (C1-C6) alkenyl, and (C1- C6) Alkynnyls are -OH, -O(C1-C4)alkyl, -O(C1-C4)alchemy Independently selected from the group consisting of nyl, -O(C1-C4)alkynyl, chlorine, and fluorine. It may be substituted with 1 to 4 substituents.

[0148] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and, wherein the formula, R' and R'' are independently, H, (C1-C6) alkyl, (C1-C6) alkenyl, or (C1-C6) alkyl It is a nyl, and the (C1-C6) alkyl, (C1-C6) alkenyl, and (C1- C6) Alkynyl is a group of 1 to 4 units independently selected from -OH and -O(CH3) It may be substituted with a substitution element.

[0149] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and, wherein the formula, R' and R'' are independently, H, (C1-C4) alkyl, (C1-C4) alkenyl, or (C1-C4) alkyl It is a nyl, and the (C1-C4) alkyl, (C1-C4) alkenyl, and (C1- C4) Alkynyl is one or two independently selected from -OH and -O(CH3). It may be substituted with one substituent.

[0150] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and, wherein the formula, R' and R'' are independently, H and (C1-C4)alkyl, wherein the (C1-C4)alkyl is -OH and -O(CH3) may be substituted with one or two substituents independently selected from -O(CH3). .

[0151] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and, wherein the formula, R' and R'' are independently, It consists of H and (C1-C4) alkyl groups.

[0152] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and the formula, where R' and R'' are, Together with the nitrogen atom it is bonded to, it forms a (C3-C6) heterocycloalkyl group. The (C3-C6) heterocycloalkyl group is formed, and the (C3-C6) heterocycloalkyl group is -OH, -O(C1-C4) Chlorine, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, and f It may be substituted with 1 to 4 substituents independently selected from the group consisting of ions.

[0153] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and in the formula, R a H, -OH, (C1-C 6) Alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, -O(C1-C 6) Alkyl, -O(C1-C6)alkenyl, -O(C1-C6)alkynyl, chlorine, Fluorine, or NR'R'', and the (C1-C6) alkyl, (C1-C6) Kenyl, (C1-C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C6) Alkenyls and -O(C1-C6)alkynyls are -OH, -O(C1-C4)alkynyls. Chlorine, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, and f It may be substituted with 1 to 4 substituents independently selected from the group consisting of ions.

[0154] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and in the formula, R a H, -OH, (C1-C 4) Alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, -O(C1-C 4) Alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, Fluorine, or NR'R'', and the (C1-C4) alkyl, (C1-C4) Kenyl, (C1-C4)alkynyl, -O(C1-C4)alkyl, -O(C1-C4) Alkenyls and -O(C1-C4)alkynyls are -OH, -O(C1-C4)al Chlorine, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, and f It may be substituted with one or two substituents independently selected from the group consisting of ions. .

[0155] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and in the formula, R a H, -OH, (C1-C 4) Alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, -O(C1-C 4) Alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, Fluorine, or NR'R'', and the (C1-C4) alkyl, (C1-C4) Kenyl, (C1-C4)alkynyl, -O(C1-C4)alkyl, -O(C1-C4) Alkenyls and -O(C1-C4)alkynyls are -OH, -O(C1-C4)al Chlorine, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, and f It may be substituted with one or two substituents independently selected from the group consisting of ions. .

[0156] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and in the formula, R a H, -OH, (C1-C 4) Alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, -O(C1-C 4) Alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, It is fluorine, or NR'R''.

[0157] In some embodiments, the compounds of the present invention are represented by the structure shown in formula I, where , R a It is NR'R''.

[0158] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and in the formula, R a It is NR'R''.

[0159] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where R' is H and R'' is pliers It is.

[0160] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, in the formula, R' is H and R'' is butyl That is the case.

[0161] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where R' is H and R'' is propyl It is.

[0162] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where R' is H and R'' is ethyl. That is the case.

[0163] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where R' is H and R'' is methyl That is the case.

[0164] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where R' is H and R'' is H ru.

[0165] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and in the formula, R a’ H, -OH, (C1- C4) alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, -O(C1- C4) alkyl, -O(C1-C4) alkenyl, -O(C1-C4) alkynyl, chlorine , fluorine, or NR'R'', and the (C1-C4) alkyl, (C1-C4) Lukenyl, (C1-C4)alkynyl, -O(C1-C4)alkyl, -O(C1-C4 Alkenyls and -O(C1-C4)alkynyls are -OH, -O(C1-C4) Lukyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, and It may be substituted with one or two substituents independently selected from the group consisting of fluorine. stomach.

[0166] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and in the formula, R a’ H, -OH, (C1- C4) alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, -O(C1- C4) alkyl, -O(C1-C4) alkenyl, -O(C1-C4) alkynyl, chlorine , fluorine, or NR'R'', and the (C1-C4) alkyl, (C1-C4) Lukenyl, (C1-C4)alkynyl, -O(C1-C4)alkyl, -O(C1-C4 Alkenyls and -O(C1-C4)alkynyls are -OH, -O(C1-C4) Lukyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, and It may be substituted with one or two substituents independently selected from the group consisting of fluorine. stomach.

[0167] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and in the formula, R a’ H, -OH, (C1- C4) alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, -O(C1- C4) alkyl, -O(C1-C4) alkenyl, -O(C1-C4) alkynyl, chlorine , fluorine, or NR'R''.

[0168] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and in the formula, R a’ It is NR'R''.

[0169] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where R' is H and R'' is pliers It is.

[0170] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, in the formula, R' is H and R'' is butyl That is the case.

[0171] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where R' is H and R'' is propyl It is.

[0172] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where R' is H and R'' is ethyl. That is the case.

[0173] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where R' is H and R'' is methyl That is the case.

[0174] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where R' is H and R'' is H ru.

[0175] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and in the formula, R a’’ H, -OH, (C1 -C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O(C1 -C6)alkyl, -O(C1-C6)alkenyl, -O(C1-C6)alkynyl, salt It is element, fluorine, or NR'R'', and the (C1-C6) alkyl, (C1-C6) Alkenyl, (C1-C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C 6) Alkenyls and -O(C1-C6) alkynyls are -OH, -O(C1-C4) Alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, and Even if substituted with one or two substituents independently selected from the group consisting of bifluorine good.

[0176] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and in the formula, R a’’ H, -OH, (C1 -C4)alkyl, (C1-C4)alkenyl, (C1-C4)alkynyl, -O(C1 -C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, salt It is element, fluorine, or NR'R'', and the (C1-C4) alkyl, (C1-C4) Alkenyl, (C1-C4)alkynyl, -O(C1-C4)alkyl, -O(C1-C 4) Alkenyls and -O(C1-C4)alkynyls are -OH, -O(C1-C4) Alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, and Even if substituted with one or two substituents independently selected from the group consisting of bifluorine good.

[0177] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and in the formula, R a’’ H, -OH, (C1 -C4)alkyl, (C1-C4)alkenyl, (C1-C4)alkynyl, -O(C1 -C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, salt It is an element, fluorine, or NR'R''.

[0178] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and in the formula, R a’’ It is NR'R''.

[0179] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where R' is H and R'' is pliers It is.

[0180] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, in the formula, R' is H and R'' is butyl That is the case.

[0181] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where R' is H and R'' is propyl It is.

[0182] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where R' is H and R'' is ethyl. That is the case.

[0183] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where R' is H and R'' is methyl That is the case.

[0184] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where R' is H and R'' is H ru.

[0185] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and in the formula, R a’’ H is H.

[0186] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and in the formula, R b H, -OH, (C1-C 6) Alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, -O(C1-C 6) Alkyl, -O(C1-C6)alkenyl, -O(C1-C6)alkynyl, chlorine, Fluorine, or NR'R'', and the (C1-C6) alkyl, (C1-C6) Kenyl, (C1-C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C6) Alkenyls and -O(C1-C6)alkynyls are -OH, -O(C1-C4)alkynyls. Chlorine, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, and f It may be substituted with one or two substituents independently selected from the group consisting of ions. .

[0187] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and in the formula, R b H, -OH, (C1-C 4) Alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, -O(C1-C 4) Alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, Fluorine, or NR'R'', and the (C1-C4) alkyl, (C1-C4) Kenyl, (C1-C4)alkynyl, -O(C1-C4)alkyl, -O(C1-C4) Alkenyls and -O(C1-C4)alkynyls are -OH, -O(C1-C4)al Chlorine, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, and f It may be substituted with one or two substituents independently selected from the group consisting of ions. .

[0188] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and in the formula, R b These are independently H, -OH, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O (C1-C6) alkyl, -O(C1-C6) alkenyl, -O(C1-C6) alkini It is chlorine, fluorine, or NR'R''.

[0189] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and in the formula, R b These are independently H, -OH, (C1-C4)alkyl, -O(C1-C4)alkyl, chlorine, fluorine, or NH2 be.

[0190] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and in the formula, R b H and O( CH3)

[0191] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where A is (C1-C6)alkyl or is a heterocycloalkyl, and the alkyl or heterocycloalkyl is -OH , oxo, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkyl Nyl, -O(C1-C6)alkyl, -O(C1-C6)alkenyl, -O(C1-C6 ) One independently selected from the group consisting of alkynyl, chlorine, fluorine, and NR'R'' It may be substituted with ~4 substituents, and the (C1-C6) alkyl, (C1-C6) Alkenyl, (C1-C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C 6) Alkenyls and -O(C1-C6) alkynyls are -OH, -O(C1-C4) Alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, and It may be substituted with 1 to 4 substituents independently selected from the group consisting of bifluorine.

[0192] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and the compound comprising, where A is (C1-C4) alkyl, or is a heterocycloalkyl, and the alkyl or heterocycloalkyl is -OH , oxo, (C1-C4) alkyl, (C1-C4) alkenyl, (C1-C4) alkyl Nyl, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4 ) One independently selected from the group consisting of alkynyl, chlorine, fluorine, and NR'R'' It may be substituted with ~4 substituents, and the (C1-C4) alkyl, (C1-C4) Alkenyl, (C1-C4)alkynyl, -O(C1-C4)alkyl, -O(C1-C 4) Alkenyls and -O(C1-C4)alkynyls are -OH, -O(C1-C4) Alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, and It may be substituted with 1 to 6 substituents independently selected from the group consisting of bifluorine.

[0193] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and, in the formula, A is a heterocycloalkyl-C (O)-R z -or (C1-C4)alkyl-N(R z ) 2 - and R z Each occurrence is They are independently H or (C1-C6) alkyl.

[0194] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and, in the formula, A is [ka] (In the formula, R zH, (C1-C6) alkyl, (C1-C6) alkenyl, (C1- C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C6)alkenyl, and Selected independently from bi-O(C1-C6)alkynyl, X is either CH or N, R d H, -OH, oxo, (C1-C4) alkyl, (C1-C4) alkenyl, (C1-C4)alkynyl, -OH, -O(C1-C4)alkyl, -O(C1-C4) Independently selected from alkenyl, -O(C1-C4)alkynyl, chlorine, and fluorine. , n is 0, 1, 2, 3, or 4. p is selected from 0, 1, 2, 3, or 4.

[0195] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and, in the formula, A is [ka] (In the formula, R z H, (C1-C6) alkyl, (C1-C6) alkenyl, and ( C1-C6) Selected independently from alkinyl, X is either CH or N, R d is -OH, (C1-C4)alkyl, -O(C1-C4)alkyl, chlorine, and Selected independently of fluorine, n is 0, 1, 2, or 3. p is selected from 0, 1, or 2.

[0196] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and, in the formula, A is [ka] (In the formula, R z These are independently H or (C1-C6) alkyl, X is either CH or N, R d is -OH, (C1-C4)alkyl, -O(C1-C4)alkyl, chlorine, and Selected independently of fluorine, n is 0, 1, 2, or 3. p is selected from 0, 1, or 2.

[0197] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and, in the formula, A is [ka] (In the formula, R z These are independently H or (C1-C6) alkyl, R d is -OH, (C1-C4)alkyl, -O(C1-C4)alkyl, chlorine, and Selected independently of fluorine, n is 0, 1, 2, or 3. p is selected from 0, 1, or 2.

[0198] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and, in the formula, A is [ka] (In the formula, R z It is independently selected from H or (C1-C6) alkyl. .

[0199] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and, in the formula, B is [ka] Selected from.

[0200] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and, in the formula, B is [ka] That is the case.

[0201] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where D is (C6-C 20 ) alkyl , (C6-C 20 ) Alkenyl, or (C6-C 20 ) is an alkynyl, and the above (C 6-C 20 ) alkyl, (C6-C 20 ) Alkenyl, or (C6-C 20 ) Aruki Nyl is one to six molecules independently selected from -OH, -O(CH3), chlorine, and fluorine. It may be substituted with a substituent, or D is [ka] (In the formula, Z is (C6-C 20 ) alkyl, (C6-C 20 ) Alkenyl, and (C 6-C 20 ) Selected from alkynyl, and the above (C6-C 20 ) alkyl, (C6-C 20 ) alkenyl, and (C6-C 20 Alkynnyls are -OH, -O(CH3), chlorine, (and may be substituted with 1 to 6 substituents independently selected from fluorine) .

[0202] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and includes, where D is (C6-C 20 ) alkyl, (C6-C 20 ) Alkenyl, or (C6-C 20 ) is alkinyl, or D is [ka] (In the formula, Z is (C6-C 20 ) alkyl, (C6-C 20 ) alkenyl, and (C6 -C 20 (Selected from Alkinil).

[0203] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and, in the formula, D is [ka] (In the formula, any carbon on the lipid chain is replaced with -OH, -O(CH3), chlorine, or fluorine) Even if it has been replaced, [ka] This is cis or trans stereochemistry, X is O, C(R) 2 , or NR, R is H, (C1-C4) alkyl, (C1-C4) alkenyl, (C1-C4) Quinyl, -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O( Selected from C1-C4) alkynyl, chlorine, and fluorine (independently selected from these). .

[0204] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and a compound of formula I. The compound represented by the structure described, and, in the formula, D is [ka] (In the formula, any carbon on the lipid chain is substituted with -OH, -O(CH3), chlorine, or fluorine.) Even if it is done, [ka] This is cis or trans stereochemistry, X 1 is -O-, -C(R) 2 -, or -NR- Each appearance of R is H, (C1-C4)alkyl, (C1-C4)alkenyl, (C1-C 4) Alkynyl, -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl Independently selected from -O(C1-C4)alkynyl, chlorine, and fluorine, n is 0, 1, 2, 3, 4, or 5. q is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9. s is 0, 1, 2, 3, 4, 5, 6, 7, or 8. t is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 1 It is selected from (which is 8).

[0205] In some embodiments, the compositions of the present invention comprise one or more Streptococcus pneumoniae antigens and formula Ia The compound represented by the structure described above includes: [ka] (In the formula, R' and R'' are H, (C1-C6) alkyl, (C1-C6) alkenyl, and A (C1-C6) alkyl, (C) is independently selected from (C1-C6)alkynyl. (C1-C6) alkenyls and (C1-C6) alkynyls are -OH, -O(C1-C4 )alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, It may also be substituted with 1 to 4 substituents independently selected from the group consisting of fluorine. , or R' and R'', together with the nitrogen they are bound to, bind together. (C3-C6) heterocycloalkyl is formed, and the (C3-C6) heterocycloalkyl Kill is -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O( C1-C4) 1-4 independently selected from the group consisting of alkynyl, chlorine, and fluorine. It may be substituted with one substituent, R b Each occurrence is -O(C1-C4)alkyl, and the aforementioned -O(C1-C4)alkyl The letters are -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C 1-C4) One independently selected from the group consisting of alkynyl, chlorine, and fluorine It may be substituted with two substituents, A is [ka] Selected from, R z Each occurrence is independently H or (C1-C6) alkyl. R d Each occurrence is -OH, (C1-C4)alkyl, -O(C1-C4)alkyl, salt Selected independently from elements and fluorine, B is [ka] And, D is [ka] A lipid chain selected from, where any carbon on the lipid chain is -OH, -O(C1-C4) Alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine, also It may be substituted with fluorine, [ka] It is cis or trans stereochemistry, X 1 is -O-, -C(R) 2 -, or -NR- Each appearance of R is H, (C1-C4)alkyl, (C1-C4)alkenyl, (C1-C 4) Alkynyl, -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl Independently selected from -O(C1-C4)alkynyl, chlorine, and fluorine, m is 0, 1, or 2. n is 0, 1, 2, or 3. p is 0, 1, or 2. q is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9. s is 1, 2, 3, 4, 5, 6, 7, or 8. t is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 1 (It is 8).

[0206] In some embodiments, the compositions of the present invention comprise one or more Streptococcus pneumoniae antigens and formula Ia The compound is represented by the structure described in [the formula], and includes [the compound], where m is 2.

[0207] In some embodiments, the compositions of the present invention comprise one or more Streptococcus pneumoniae antigens and formula Ia The compound is represented by the structure described in [the formula], and includes [the compound], where m is 1.

[0208] In some embodiments, the compositions of the present invention comprise one or more Streptococcus pneumoniae antigens and formula Ia The compound is represented by the structure described in [the given formula], and includes [the given formula], where m is 0.

[0209] In some embodiments, the compositions of the present invention comprise one or more Streptococcus pneumoniae antigens and formula Ia The compound represented by the structure described above, and includes, where R' and R'' are H and (C1-C6) alkyl groups are independently selected, and the alkyl group has 1 to 4 -OH groups. It may be substituted with bi or -O(CH3).

[0210] In some embodiments, the compositions of the present invention comprise one or more Streptococcus pneumoniae antigens and formula Ia The compound represented by the structure described above, and includes, where R' and R'' are H and (C1-C4) alkyl groups are independently selected, and the alkyl group consists of -OH and -O(C It may be substituted with 1 to 4 substituents independently selected from H3).

[0211] In some embodiments, the compositions of the present invention comprise one or more Streptococcus pneumoniae antigens and formula Ia The compound is represented by the structure described in the formula, and includes, where R' is H and R'' is penetrant. It's chill.

[0212] In some embodiments, the compositions of the present invention comprise one or more Streptococcus pneumoniae antigens and formula Ia The compound is represented by the structure described below, and includes, where R' is H and R'' is buty It is.

[0213] In some embodiments, the compositions of the present invention comprise one or more Streptococcus pneumoniae antigens and formula Ia The compound is represented by the structure described below, and includes, where R' is H and R'' is pro It's a pill.

[0214] In some embodiments, the compositions of the present invention comprise one or more Streptococcus pneumoniae antigens and formula Ia The compound is represented by the structure described below, and includes, where R' is H and R'' is ethyl acetate. It is.

[0215] In some embodiments, the compositions of the present invention comprise one or more Streptococcus pneumoniae antigens and formula Ia The compound is represented by the structure described below, and includes, where R' is H and R'' is methyl It is.

[0216] In some embodiments, the compositions of the present invention comprise one or more Streptococcus pneumoniae antigens and formula Ia The compound represented by the structure described above includes, where R' is H and R'' is H be.

[0217] In some embodiments, the compositions of the present invention comprise one or more Streptococcus pneumoniae antigens and formula Ia A compound represented by the structure described above, and in the formula, R a’’ is H or (C1- C4) Alkyl, wherein the alkyl is independently selected from one or two -OH groups. It may also be substituted with -O(CH3).

[0218] In some embodiments, the compositions of the present invention comprise one or more Streptococcus pneumoniae antigens and formula Ia A compound represented by the structure described above, and in the formula, R a’’ is H or (C1-C 4) It is alkyl.

[0219] In some embodiments, the compositions of the present invention comprise one or more Streptococcus pneumoniae antigens and formula Ia A compound represented by the structure described above, and in the formula, R a’’ H is H.

[0220] In some embodiments, the compositions of the present invention comprise one or more Streptococcus pneumoniae antigens and formula Ia A compound represented by the structure described above, and in the formula, R b is -O(C1-C4)a The -O(C1-C4) alkyl group is independently selected from one or two other groups. It may be substituted with -OH or -O(CH3).

[0221] In some embodiments, the compositions of the present invention comprise one or more Streptococcus pneumoniae antigens and formula Ia A compound represented by the structure described above, and in the formula, R b It is -O(CH3).

[0222] In some embodiments, the compositions of the present invention comprise one or more Streptococcus pneumoniae antigens and formula Ia The compound is represented by the structure described in the formula, and includes, where A is [ka] Selected from, R z These are independently H or (C1-C6) alkyl.

[0223] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II The compound represented by the structure described above includes: [ka] (In the formula, R 1 is a (C1-C6) alkyl group, and the (C1-C6) alkyl group has -OH group It may be substituted with 1 to 4 substituents independently selected from -O(CH3), R 2 is H, methyl or -O(CH3), R 3Each occurrence is independently H, (C1-C4) alkyl, and (C1-C4) alkenyl. , (C1-C4)alkynyl, or -O(C1-C4)alkyl, and the (C1- C4) alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, or -O( C1-C4) alkyl is independently selected from -OH and -O(CH3) It may be substituted with two substituents, R 4 Each occurrence is independently H, (C1-C4) alkyl, and (C1-C4) alkenyl. , (C1-C4)alkynyl, or -O(C1-C4)alkyl, and the (C1- C4) alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, or -O( C1-C4) alkyl is independently selected from -OH and -O(CH3) It may be substituted with two substituents, R 5 teeth, [ka] And, R 6 (C6-C 20 ) alkyl, (C6-C 20 ) alkenyl, and (C6-C 20 ) Selected from alkynyl, and the above (C6-C 20 ) alkyl, (C6-C 20 ) Al Kenil, and (C6-C 20 Alkynyl is -OH, -O(C1-C4)alkyl, -O(C1-C4) alkenyl, -O(C1-C4) alkynyl, chlorine, and fluorine They may be substituted with 1 to 6 substituents that are independently selected. Each occurrence of n is 4.

[0224] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II The compound represented by the structure described herein, and each occurrence of n is independently 0, 1, 2 , or 3.

[0225] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II The compound represented by the structure described herein, and each occurrence of n is independently 0, 1, and The answer is 2.

[0226] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II The compound represented by the structure described herein, and each occurrence of n is independently either 0 or 1. That is the case.

[0227] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II The compound is represented by the structure described in [the given formula], and includes [the given formula], where n is absent.

[0228] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 1 ethyl, butyl (branched) (or linear), or pentyl (branched or linear), and the ethyl, butyl, Pentyl is independently selected from -OH, -O(CH3), chlorine, and fluorine. It may be substituted with 1 to 4 substituents.

[0229] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 1 butyl (branched or linear) ) and the butyl is independently selected from -OH, -O(CH3), chlorine, and fluorine. It may be substituted with one to four selected substituents.

[0230] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 1 ethyl, butyl (branched) (or linear), or pentyl (branched or linear), and the ethyl, butyl, Alternatively, pentyl is one or two molecules independently selected from -OH and -O(CH3). They may be substituted with substituents.

[0231] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 1 butyl (branched chain or straight chain) The chain is such that the butyl is independently selected from -OH and -O(CH3). Alternatively, it may be substituted with two substituents.

[0232] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 2 It is either H or methyl.

[0233] In some embodiments, the compounds of the present invention are represented by the structure shown in Formula II, Medium, R 2 H is H.

[0234] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 3 Each occurrence of is independent, ( C1-C4) alkyl, (C1-C4) alkenyl, or -O(C1-C4) alkyl The (C1-C4) alkyl, (C1-C4) alkenyl, or -O(C1- C4) Alkyl is one to four substitutions independently selected from -OH or -O(CH3). It may be substituted with the base.

[0235] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 3 Each occurrence of is independent, ( It is C1-C4)alkyl or -O(C1-C4)alkyl, and the (C1-C4) Alkyl or -O(C1-C4) alkyl groups are independent of -OH or O(CH3). It may be substituted with one to four selected substituents.

[0236] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 3 Each occurrence of is independent, ( It is C1-C4)alkyl or -O(C1-C4)alkyl, and the (C1-C4) Alkyl or -O(C1-C4) alkyl groups are independent of -OH or O(CH3). It may be substituted with one or two selected substituents.

[0237] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 3 Each occurrence is independent of the last one. It is chill or -O(CH3).

[0238] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 3 Each occurrence is -O(CH3 )

[0239] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 4 Each occurrence of is independent, ( It is C1-C4)alkyl or -O(C1-C4)alkyl, and the (C1-C4) Alkyl or -O(C1-C4)alkyl groups are -OH, -O(CH3), chlorine, and f It may be substituted with 1 to 4 substituents independently selected from the element.

[0240] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 4 Each occurrence of is independent, ( It is C1-C4) alkyl or -O(C1-C4) alkyl.

[0241] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 6 (C6-C 20 ) Al Kill and (C6-C 20 ) Selected from alkenyls, and the above (C6-C 20 ) Alkyl Call (C6-C 20 The alkenyl is independently selected from -OH and -O(CH3). It may be substituted with 1 to 6 substituents.

[0242] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 6 (C8-C 20 ) Al Kill and (C8-C 20 ) Selected from alkenyls, and the above (C8-C 20 ) Alkyl Call (C8-C 20 The alkenyl is independently selected from -OH and -O(CH3). It may be substituted with 1 to 6 substituents.

[0243] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 6 is, (C 10 -C 20 )a Lukil and (C 10 -C 20 ) Selected from alkenyls, and the (C 10 -C 20 ) Al Kill and (C 10 -C 20 Alkenyls are independent of -OH and -O(CH3) It may be substituted with 1 to 6 selected substituents.

[0244] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 6 is, (C 12 -C 20 )a Lukil and (C 12 -C 20 ) Selected from alkenyls, and the (C 12 -C 20 ) Al Kill and (C 12 -C 20 Alkenyls are independent of -OH and -O(CH3) It may be substituted with 1 to 6 selected substituents.

[0245] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 6 is, (C 14 -C 20 )a Lukil and (C 14 -C 20 ) Selected from alkenyls, and the (C 14 -C 20 ) Al Kill and (C 14 -C 20 Alkenyls are independent of -OH and -O(CH3) It may be substituted with 1 to 6 selected substituents.

[0246] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 6 is, (C 16 -C 20 )a Lukil and (C 16 -C 20 ) Selected from alkenyls, and the (C 16 -C 20 ) Al Kill and (C 16 -C 20 Alkenyls are independent of -OH and -O(CH3) It may be substituted with 1 to 6 selected substituents.

[0247] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 6 (C6-C 20 ) Al Kill and (C6-C 20 ) Selected from Alkenil.

[0248] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 6 (C8-C 20 ) Aruki Lu and (C8-C 20 ) Selected from Alkenil.

[0249] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 6 is (C 10 -C 20 ) Al Kill and (C 10 -C 20 ) Selected from Alkenil.

[0250] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 6 is, (C 12 -C 20 )a Lukil and (C 12 -C 20 ) Selected from Alkenil.

[0251] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 6 is (C 14 -C 20 ) Al Kill and (C 14 -C 20 ) Selected from Alkenil.

[0252] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described above, and in the formula, R 6 is, (C 16 -C20 )a Lukil and (C 16 -C 20 ) Selected from Alkenil.

[0253] The present invention further provides compositions comprising a compound having the structure described in formula IIa: [ka] (In the formula, R 1 is butyl, and the butyl may be substituted with one or two -OH groups. Ku, R 3 Each occurrence is independently either H or -O(CH3), R 5 teeth, [ka] And, R 6 is, (C 10 -C 20 ) alkyl, (C 10 -C 20 ) alkenyl, and (C1 0-C 20 (Selected from Alkinil).

[0254] In some embodiments, the compounds of the present invention are represented by the structure described in formula IIa, In the formula, R 6 is, (C 10 -C 20 )alkyl and (C 10 -C 20 ) Selected from Alkenil Selected, and the above (C 10 -C 20 )alkyl and (C 10 -C 20 ) Alkenyl is -O Substituted with one or two substituents independently selected from H and -O(CH3) That's fine.

[0255] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in a, and in the formula, R 6 is, (C 12 -C 20 ) Alkyl and (C 12 -C 20 ) Selected from alkenyls, and the (C 12 -C 20 )a Lukil and (C 12 -C 20 Alkenyls are independent of -OH and -O(CH3). It may be substituted with one or two substituents selected by the process.

[0256] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in a, and in the formula, R 6 is, (C 14 -C 20 ) Alkyl and (C 14 -C 20 ) Selected from alkenyls, and the (C 14 -C 20 )a Lukil and (C 14 -C 20 Alkenyls are independent of -OH and -O(CH3). It may be substituted with one or two substituents selected by the process.

[0257] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in a, and in the formula, R 6 is, (C 16 -C 20 ) Alkyl and (C 16 -C 20 ) Selected from alkenyls, and the (C 16 -C 20 )a Lukil and (C 16 -C 20 Alkenyls are independent of -OH and -O(CH3). It may be substituted with one or two substituents selected by the process.

[0258] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in a, and in the formula, R 6 is, (C 10 -C 20 ) Alkyl and (C 10 -C 20 ) Selected from Alkenil.

[0259] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in a, and in the formula, R 6 is, (C 12 -C 20 ) Alkyl and (C 12 -C 20 ) Selected from Alkenil.

[0260] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in a, and in the formula, R 6 is, (C 14 -C 20 ) Alkyl and (C 14 -C 20 ) Selected from Alkenil.

[0261] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in a, and in the formula, R 6 is, (C 16 -C 20 ) Alkyl and (C 16 -C20 ) Selected from Alkenil.

[0262] The present invention provides a composition comprising a compound having the structure described in Formula III: [ka] (In the formula, R 1 is a (C1-C6) alkyl group, and the (C1-C6) alkyl group has -OH group It may be substituted with 1 to 4 substituents independently selected from -O(CH3), R 2 is H, methyl or -O(CH3), R 3 Each occurrence is independently H, (C1-C4) alkyl, and (C1-C4) alkenyl. , (C1-C4)alkynyl, or -O(C1-C4)alkyl, and the (C1- C4) alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, or -O( C1-C4) alkyl is independently selected from -OH and -O(CH3) It may be substituted with two substituents, R 4 (C6-C 20 ) alkyl, (C6-C 20 ) alkenyl, and (C6-C 20 ) Selected from alkynyl, and the above (C6-C 20 ) alkyl, (C6-C 20 ) Al Kenil, and (C6-C 20 Alkynyl is -OH, -O(C1-C4)alkyl, -O(C1-C4) alkenyl, -O(C1-C4) alkynyl, chlorine, and fluorine They may be substituted with 1 to 6 substituents that are independently selected. n is 4).

[0263] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II The compound is represented by the structure described in I, and includes, where n is 0, 1, 2, or 3. be.

[0264] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II The compound is represented by the structure described in I, and the formula is such that n is 0, 1, or 2. .

[0265] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II The compound includes the structure represented by the structure described in I, where n is 0 or 1.

[0266] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II The compound is represented by the structure described in I, and includes, where n is absent in the formula.

[0267] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 1 is ethyl, butyl (min (branched or linear), or pentyl (branched or linear), and the ethyl, butyl, Alternatively, pentyl is independently selected from -OH, -O(CH3), chlorine, and fluorine. It may be substituted with 1 to 4 substituents.

[0268] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 1 is butyl (branched or straight The chain is, and the butyl is independently of -OH, -O(CH3), chlorine, and fluorine. It may be substituted with one to four selected substituents.

[0269] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 1 is ethyl, butyl (min (branched or linear), or pentyl (branched or linear), and the ethyl, butyl, Alternatively, pentyl is one or two of the -OH and -O(CH3) groups selected independently. It may be substituted with a substituent.

[0270] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 1 is butyl (branched chain or (Straight chain), and the butyl is one independently selected from -OH and -O(CH3) Alternatively, it may be substituted with two substituents.

[0271] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 2 is H or methyl .

[0272] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 2 H is H.

[0273] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 3 Each occurrence is independent, (C1-C4)alkyl, (C1-C4)alkenyl, or -O(C1-C4)alkyl It is a (C1-C4) alkyl, (C1-C4) alkenyl, or -O(C1 -C4) alkyl is one to four positions independently selected from -OH or -O(CH3) It may be substituted with a substitution element.

[0274] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 3 Each occurrence is independent, (C1-C4)alkyl or -O(C1-C4)alkyl, and the above (C1-C4) Alkyl or -O(C1-C4)alkyl groups are independent of -OH or -O(CH3). It may be substituted with 1 to 4 substituents selected by the process.

[0275] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 3 Each occurrence is independent, (C1-C4)alkyl or -O(C1-C4)alkyl, and the above (C1-C4) Alkyl or -O(C1-C4)alkyl groups are independent of -OH or -O(CH3). It may be substituted with one or two substituents selected by the process.

[0276] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 3 Each occurrence is independent, It is methyl or -O(CH3).

[0277] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 3 Each occurrence is -O(CH 3)

[0278] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 4 (C6-C 20 )a Lukil and (C6C 20 ) Selected from alkenyls, and the above (C6-C 20 ) alkyl and (C6-C 20 The alkenyl group is independently selected from -OH and -O(CH3). It may be substituted with 1 to 6 substituents.

[0279] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 4 (C8-C 20 )a Lukil and (C8C 20 ) Selected from alkenyls, and the above (C8-C 20 ) alkyl and (C8-C 20 The alkenyl group is independently selected from -OH and -O(CH3). It may be substituted with 1 to 6 substituents.

[0280] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 4 is, (C 10 -C 20 ) Alkyl and (C 10 -C 20) Selected from alkenyls, and the (C 10 -C 20 )a Lukil and (C 10 -C 20 Alkenyls are independent of -OH and -O(CH3). It may be substituted with 1 to 6 substituents selected by the process.

[0281] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 4 is, (C 12 -C 20 ) Alkyl and (C 12 -C 20 ) Selected from alkenyls, and the (C 12 -C 20 )a Lukil and (C 12 -C 20 Alkenyls are independent of -OH and -O(CH3). It may be substituted with 1 to 6 substituents selected by the process.

[0282] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 4 is, (C 14 -C 20 ) Alkyl and (C 14 -C 20 ) Selected from alkenyls, and the (C 14 -C 20 )a Lukil and (C 14 -C 20 Alkenyls are independent of -OH and -O(CH3). It may be substituted with 1 to 6 substituents selected by the process.

[0283] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 4 is, (C 16 -C 20 ) Alkyl and (C 16 -C 20 ) Selected from alkenyls, and the (C 16 -C 20 )a Lukil and (C 16 -C 20 Alkenyls are independent of -OH and -O(CH3). It may be substituted with 1 to 6 substituents selected by the process.

[0284] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 4 (C6-C 20 )a Lukil and (C6C 20 ) Selected from Alkenil.

[0285] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 4 (C8-C 20 )a Lukil and (C8C 20 ) Selected from Alkenil.

[0286] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 4 is, (C 10 -C 20 ) Alkyl and (C 10 -C 20 ) Selected from Alkenil.

[0287] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 4 is, (C 12 -C 20 ) Alkyl and (C 12 -C 20 ) Selected from Alkenil.

[0288] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 4 is, (C 14 -C 20 ) Alkyl and (C 14 -C 20 ) Selected from Alkenil.

[0289] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in I, and in the formula, R 4 is, (C 16 -C 20 ) Alkyl and (C 16 -C 20 ) Selected from Alkenil.

[0290] The present invention also provides compositions comprising compounds having the structure described in formula IIIa: [ka] (In the formula, R 1 is butyl, and the butyl may be substituted with one or two -OH groups. Ku, R 3 Each occurrence is independently either H or -O(CH3), R 4 is, (C 10 -C 20 ) alkyl, (C10 -C 20 ) alkenyl, and (C1 0-C 20 (Selected from Alkinil).

[0291] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in Ia, and in the formula, R 4 (C6-C 20 ) Alkyl and (C6-C 20 ) Selected from alkenyls, and the above (C6-C 20 ) Aruki Lu and (C6C 20 The alkenyl group is independently selected from -OH and -O(CH3). It may be substituted with 1 to 6 substituents.

[0292] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in Ia, and in the formula, R 4 (C8-C 20 ) Alkyl and (C8-C 20 ) Selected from alkenyls, and the above (C8-C 20 ) Aruki Lu and (C8-C 20 The alkenyl group is independently selected from -OH and -O(CH3). It may be substituted with 1 to 6 substituents.

[0293] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in Ia, and in the formula, R 4 is, (C 10 -C 20 )alkyl and (C 10 -C 20 ) Selected from alkenyls, and the (C 10 -C 20) Alkyl and (C 10 -C 20 Alkenyls are independent of -OH and -O(CH3). It may be substituted with 1 to 6 substituents selected by the process.

[0294] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in Ia, and in the formula, R 4 is, (C 12 -C 20 )alkyl and (C 12 -C 20 ) Selected from alkenyls, and the (C 12 -C 20 ) Alkyl and (C 12 -C 20 Alkenyls are independent of -OH and -O(CH3). It may be substituted with 1 to 6 substituents selected by the process.

[0295] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in Ia, and in the formula, R 4 is, (C 14 -C 20 )alkyl and (C 14 -C 20 ) Selected from alkenyls, and the (C 14 -C 20 ) Alkyl and (C 14 -C 20 Alkenyls are independent of -OH and -O(CH3). It may be substituted with 1 to 6 substituents selected by the process.

[0296] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in Ia, and in the formula, R 4is, (C 16 -C 20 )alkyl and (C 16 -C 20 ) Selected from alkenyls, and the (C 16 -C 20 ) Alkyl and (C 16 -C 20 Alkenyls are independent of -OH and -O(CH3). It may be substituted with 1 to 6 substituents selected by the process.

[0297] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in Ia, and in the formula, R 4 (C6-C 20 ) Alkyl and (C6-C 20 ) Selected from Alkenil.

[0298] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in Ia, and in the formula, R 4 (C8-C 20 ) Alkyl and (C8-C 20 ) Selected from Alkenil.

[0299] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in Ia, and in the formula, R 4 is, (C 10 -C 20 )alkyl and (C 10 -C 20 ) Selected from Alkenil.

[0300] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in Ia, and in the formula, R 4 is, (C 12 -C 20 )alkyl and (C 12 -C 20 ) Selected from Alkenil.

[0301] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in Ia, and in the formula, R 4 is, (C 14 -C 20 )alkyl and (C 14 -C 20 ) Selected from Alkenil.

[0302] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula II A compound represented by the structure described in Ia, and in the formula, R 4 is, (C 16 -C 20 )alkyl and (C 16 -C 20 ) Selected from Alkenil.

[0303] The present invention provides a composition comprising a compound having the structure described in Formula IV: [ka] (In the formula, R 1 is a (C1-C6) alkyl group, and the (C1-C6) alkyl group has -OH group It may be substituted with 1 to 4 substituents independently selected from -O(CH3), R 2 is H, methyl or -O(CH3), R 3 Each occurrence is independently H, (C1-C4) alkyl, and (C1-C4) alkenyl. , (C1-C4)alkynyl, or -O(C1-C4)alkyl, and the (C1- C4) alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, and -O( C1-C4) alkyl is independently selected from -OH and -O(CH3) It may be substituted with two substituents, R 4 Each occurrence is (C6-C 20 ) alkyl, (C6-C 20 ) Alkenil, and ( C6-C 20 ) independently selected from alkynyl, and the (C6-C 20 ) alkyl, (C 6-C 20 ) alkenyl, and (C6-C 20 Alkinyl is -OH, -O(C1- C4) alkyl, -O(C1-C4) alkenyl, -O(C1-C4) alkynyl, chlorine or may be substituted with 1 to 6 substituents independently selected from fluorine. n is 4).

[0304] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV The compound is represented by the structure described in the formula, and includes, where n is 0, 1, 2, or 3. ru.

[0305] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV The compound comprises the structure represented by the structure described in [the formula], where n is 0, 1, or 2.

[0306] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV The compound comprises the structure represented by the structure described in [the given formula], where n is 0 or 1.

[0307] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV The compound is represented by the structure described in [the given formula], and includes [the given formula], where n is absent.

[0308] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 1 ethyl, butyl (branched) (or linear) or pentyl (branched or linear), and the ethyl, butyl, Pentyl is independently selected from -OH, -O(CH3), chlorine, and fluorine. It may be substituted with up to four substituents.

[0309] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 1 is butyl (branched or straight The chain is, and the butyl is independently of -OH, -O(CH3), chlorine, and fluorine. It may be substituted with one to four selected substituents.

[0310] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 1 ethyl, butyl (branched) (or linear), or pentyl (branched or linear), and the ethyl, butyl, Alternatively, pentyl is one or two molecules independently selected from -OH and -O(CH3). They may be substituted with substituents.

[0311] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R1 is butyl (branched or straight The chain is such that the butyl is independently selected from -OH and -O(CH3). Alternatively, it may be substituted with two substituents.

[0312] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 2 It is either H or methyl.

[0313] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 2 H is H.

[0314] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 3 (C1-C 4) Alkyl, (C1-C4)alkenyl, or -O(C1-C4)alkyl, The aforementioned (C1-C4) alkyl, (C1-C4) alkenyl, or -O(C1-C4) Lukil is substituted with 1 to 4 substituents independently selected from -OH or -O(CH3). It's fine if it is done.

[0315] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and R 3 Each occurrence of (C1- It is C4)alkyl or -O(C1-C4)alkyl, and the (C1-C4)alkyl Alternatively, -O(C1-C4) alkyl groups are independently selected from -OH or -O(CH3). It may be substituted with 1 to 4 substituents.

[0316] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and R 3 Each occurrence of (C1- It is C4)alkyl or -O(C1-C4)alkyl, and the (C1-C4)alkyl Alternatively, -O(C1-C4) alkyl groups are independently selected from -OH or -O(CH3). It may be substituted with one or two substituents.

[0317] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 3 Each occurrence is independent of the last one. It is chill or -O(CH3).

[0318] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 3 Each occurrence is -O(CH3 )

[0319] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 4 Each occurrence is (C6-C2 0) Alkyl and (C6-C 20 ) independently selected from alkenyls, and the (C6-C 20 )alkyl and (C6-C 20 ) Alkenil consists of 1 to 6 independently selected - It may be substituted with OH or -O(CH3).

[0320] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 4 Each appearance is (C8-C2 0) alkyl and (C8-C 20 ) independently selected from alkenyls, and the (C8-C 20 )alkyl and (C8-C 20 Alkenyls are derived from -OH and -O(CH3) It may be substituted with 1 to 6 independently selected substituents.

[0321] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 4 Each occurrence is (C 10 -C 20 )alkyl and (C 10 -C 20 ) independently selected from alkenyls, and the (C1 0-C 20 )alkyl and (C 10 -C 20 Alkenyls are -OH and -O(CH 3) may be substituted with 1 to 6 substituents selected independently of the above.

[0322] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 4 Each occurrence is (C 12 -C 20 )alkyl and (C 12 -C 20 ) independently selected from alkenyls, and the (C1 2-C 20 )alkyl and (C 12 -C 20 Alkenyls are -OH and -O(CH 3) may be substituted with 1 to 6 substituents selected independently of the above.

[0323] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 4 Each occurrence is (C 14 -C 20 )alkyl and (C 14 -C 20 ) independently selected from alkenyls, and the (C1 4-C 20 )alkyl and (C 14 -C 20 Alkenyls are -OH and -O(CH 3) may be substituted with 1 to 6 substituents selected independently of the above.

[0324] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 4 Each occurrence is (C 16 -C 20 )alkyl and (C 16 -C 20 ) independently selected from alkenyls, and the (C1 6-C 20 )alkyl and (C 16 -C 20 Alkenyls are -OH and -O(CH 3) may be substituted with 1 to 6 substituents selected independently of the above.

[0325] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 4 Each occurrence is (C6-C2 0) Alkyl and (C6-C 20 ) Selected independently of Alkenil.

[0326] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 4 Each appearance is (C8-C2 0) alkyl and (C8-C 20 ) Selected independently of Alkenil.

[0327] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 4 Each occurrence is (C 10 -C 20 )alkyl and (C 10 -C 20 ) Selected independently of Alkenil.

[0328] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 4 Each occurrence is (C 12 -C 20 )alkyl and (C 12 -C 20 ) Selected independently of Alkenil.

[0329] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 4 Each occurrence is (C 14 -C 20 )alkyl and (C 14 -C 20 ) Selected independently of Alkenil.

[0330] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described above, and in the formula, R 4 Each occurrence is (C 16 -C 20 )alkyl and (C 16 -C 20 ) Selected independently of Alkenil.

[0331] The present invention provides compositions comprising a compound having the structure described in formula IVa: [ka] (In the formula, R 1 is butyl, and the butyl may be substituted with one or two -OH groups. Ku, R 3 Each occurrence is independently either H or -O(CH3), R 4 Each occurrence is (C 10 -C 20 ) alkyl, (C 10 -C 20 ) Alkenil, oh bi (C 10 -C 20 (Selected independently of Alkinnil).

[0332] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described in a, and in the formula, R 4 Each occurrence is (C6-C 20 )alkyl and (C6-C 20 ) independently selected from alkenyls, and the (C6- C 20 )alkyl and (C6-C 20 Alkenyls are -OH and -O(CH3) They may be substituted with 1 to 6 substituents that are independently selected.

[0333] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described in a, and in the formula, R 4 Each occurrence is (C8-C 20 )alkyl and (C8-C 20 ) independently selected from alkenyl, and the (C8- C 20 )alkyl and (C8-C 20 Alkenyls are -OH and -O(CH3) They may be substituted with 1 to 6 substituents that are independently selected.

[0334] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described in a, and in the formula, R 4 Each occurrence is (C 10 - C 20 )alkyl and (C 10 -C 20 ) independently selected from alkenyl, and the (C 10 -C 20 )alkyl and (C 10 -C 20 Alkenyls are -OH and -O(C It may be substituted with 1 to 6 substituents independently selected from H3).

[0335] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described in a, and in the formula, R 4 Each occurrence is (C 12 - C 20 )alkyl and (C 12 -C 20 ) independently selected from alkenyl, and the (C 12 -C 20 )alkyl and (C 12 -C 20Alkenyls are -OH and -O(C It may be substituted with 1 to 6 substituents independently selected from H3).

[0336] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described in a, and in the formula, R 4 Each occurrence is (C 14 - C 20 )alkyl and (C 14 -C 20 ) independently selected from alkenyl, and the (C 14 -C 20 )alkyl and (C 14 -C 20 Alkenyls are -OH and -O(C It may be substituted with 1 to 6 substituents independently selected from H3).

[0337] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described in a, and in the formula, R 4 Each occurrence is (C 16 - C 20 )alkyl and (C 16 -C 20 ) independently selected from alkenyl, and the (C 16 -C 20 )alkyl and (C 16 -C 20 Alkenyls are -OH and -O(C It may be substituted with 1 to 6 substituents independently selected from H3).

[0338] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described in a, and in the formula, R 4 Each occurrence is (C6-C 20)alkyl and (C6-C 20 ) Selected independently of Alkenil.

[0339] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described in a, and in the formula, R 4 Each occurrence is (C8-C 20 )alkyl and (C8-C 20 ) Selected independently of Alkenil.

[0340] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described in a, and in the formula, R 4 Each occurrence is (C 10 - C 20 )alkyl and (C 10 -C 20 ) Selected independently of Alkenil.

[0341] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described in a, and in the formula, R 4 Each occurrence is (C 12 - C 20 )alkyl and (C 12 -C 20 ) Selected independently of Alkenil.

[0342] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described in a, and in the formula, R 4 Each occurrence is (C 14 - C 20 )alkyl and (C 14 -C 20 ) Selected independently of Alkenil.

[0343] In some embodiments, the composition of the present invention comprises one or more Streptococcus pneumoniae antigens and Formula IV A compound represented by the structure described in a, and in the formula, R 4 Each occurrence is (C 16 - C 20 )alkyl and (C 16 -C 20 ) Selected independently of Alkenil.

[0344] In some embodiments, the present invention includes one or more Streptococcus pneumoniae antigens, (N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[ 4,3-d]pyrimidine-2-yl(methyl)-3,5-dimethoxyphenyl)piperazi (1-yl)-5-oxopentyl) stearamide, (S)-N-(5-(4-(4-((5-amino-7-((1-hydroxypentane- 2-yl)amino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)- 3,5-Dimethoxyphenyl)piperazin-1-yl)-5-oxopentyl)stear Mido, (S)-1-(4-(4-((5-amino-7-((1-hydroxypentan-2-i (Lu)amino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3,5 -Dimethoxyphenyl)piperazine-1-yl)octadecane-1-one, N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Il)-5-oxopentyl) stearamide, N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- Il-5-oxopentyl)tetradecaneamide, N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- Il-5-oxopentyl)oleamide, (9Z,12Z)-N-(5-(4-(4-((5-amino-7-(butylamino)- 2H-Pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3-methoxyphenyl )piperazine-1-yl)-5-oxopentyl)octadeca-9,12-dienamide , N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 [3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)-1,4-diaze Pan-1-yl)-5-oxopentyl) stearamide, N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperidine-1- (Il)-5-oxopentyl) stearamide, N-(5-(3-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)azetidine-1- (Il)-5-oxopentyl) stearamide, 1-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]py Limidine-2-yl(methyl)-3-methoxyphenyl)-N-(3-stearamidopro (Pill) Piperidine-4-carboxamide, (1s,3s)-3-(2-(4-(4-((5-amino-7-(butylamino)-2 H-Pyrazolo[4,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl) Piperazine-1-yl)-2-oxoethyl)-N-octadecylcyclobutane-1-ca Ruboxamide, (1s,3s)-3-(2-(4-(4-((5-amino-7-(butylamino)-2 H-Pyrazolo[4,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl) Piperazine-1-yl)-2-oxoethyl)-N-hexadecylcyclobutane-1- Ruboxamide, N-(3-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Iyl)-3-oxopropyl) stearamide, N-(7-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Il)-7-oxoheptyl) stearamide, N-(3-(2-(4-(4-((5-amino-7-(butylamino)-2H-pyrazo Ro[4,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl(piperazine) -1-yl)-2-oxoethyl)cyclobutyl)stearamide, N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Iyl)-4,4-dimethyl-5-oxopentyl) stearamide, N-(6-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (yl)-2-methyl-6-oxohexane-2-yl)stearamide, 1-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3- d) Pyrimidine-2-yl)methyl)-3-methoxyphenyl)piperazine-1-yl) -5-(octadecyloxy)pentan-1-one, 1-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3- d) Pyrimidine-2-yl)methyl)-3-methoxyphenyl)piperazine-1-yl) -5-(octadecylamino)pentan-1-one, N-(5-(4-(4-((5-amino-7-(butylamino)-3-methyl-2H- Pyrazolo[4,3-d]pyrimidine-2-yl)methyl)3-methoxyphenyl)pipette Radin-1-yl)-5-oxopentyl) stearamide, (9Z,12Z)-N-(4-((4-((5-amino-7-(butylamino)-2H -Pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3,5-dimethoxybendi (Methyl)aminobutyl)octadeca-9,12-dieneamide, N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3 -d]pyrimidine-2-yl(methyl)-3,5-dimethoxybenzyl(methyl)amine (N)butyl)tetradecaneamide, N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3 -d]pyrimidine-2-yl(methyl)-3,5-dimethoxybenzyl(methyl)amine (N)butyl)oleamide, N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3 -d]pyrimidine-2-yl(methyl)-3,5-dimethoxybenzyl(methyl)amine (N)Butyl)Stearamide, N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3 -d]pyrimidine-2-yl(methyl)-3,5-dimethoxybenzyl(methyl)amine (no)-4-oxobutyl)stearamide, (6Z,9Z,28Z,31Z)-Heptatriaconta-6,9,28,31-Tetra En-19-yl(4-((4-((5-amino-7-(butylamino)-2H-pyrazo Ro[4,3-d]pyrimidine-2-yl(methyl)-3,5-dimethoxybenzyl)(Me Chill aminobutyl carbamate, 4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]py Limidine-2-yl(methyl)-3-methoxyphenyl)-N-(3-stearamidopro (Pill) Piperazine-1-carboxamide, 3-Stearamidopropyl 4-(4-((5-Amino-7-(butylamino)-2H- Pyrazolo[4,3-d]pyrimidine-2-yl)methyl)3-methoxyphenyl)pipette Radin-1-carboxylate, N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Iyl)-6,6,6-trifluorohexyl)stearamide, N-(4-((4-((7-(butylamino)-5-hydroxy-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3,5-dimethoxybenzyl(methyl) Amino)butyl)stearamide, and (6Z,9Z,28Z,31Z)-Heptatriaconta-6,9,28,31-Tetra En-19-yl(5-(4-(4-((5-amino-7-(butylamino)-2H-p Lazolo[4,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl(piper) Zin-1-yl)-5-oxopentyl)carbamate, A composition comprising a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof. To provide.

[0345] In some embodiments, the present invention comprises one or more Streptococcus pneumoniae antigens and (N-(5-( 4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyri Midine-2-yl)methyl)-3,5-dimethoxyphenyl)piperazin-1-yl)- A composition comprising 5-oxopentyl) stearamide, or a pharmaceutically acceptable salt thereof. To provide.

[0346] In some embodiments, the present invention comprises one or more Streptococcus pneumoniae antigens and (N-(5-( 4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyri Midine-2-yl)methyl)-3,5-dimethoxyphenyl)piperazin-1-yl)- A composition comprising 5-oxopentyl) stearamide, or a pharmaceutically acceptable salt thereof. To provide.

[0347] In some embodiments, the present invention comprises one or more Streptococcus pneumoniae antigens and (S)-N-( 5-(4-(4-((5-amino-7-((1-hydroxypentan-2-yl)amino )-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3,5-dimethyl Siphenyl)piperazin-1-yl)-5-oxopentyl)stearamide, or the same The present invention provides a composition comprising a pharmaceutically acceptable salt.

[0348] In some embodiments, the present invention comprises one or more Streptococcus pneumoniae antigens and (S)-1-( 4-(4-((5-amino-7-((1-hydroxypentan-2-yl)amino)-2 H-Pyrazolo[4,3-d]pyrimidine-2-yl(methyl)-3,5-dimethoxyphenate (Nyl)piperazine-1-yl)octadecane-1-one, or the pharmaceutically acceptable thereof The present invention provides a composition containing salt.

[0349] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and N-(5-(4 -(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrim Zin-2-yl)methyl)-3-methoxyphenyl)piperazin-1-yl)-5-oxy The present invention provides a composition comprising sopentyl stearamide or a pharmaceutically acceptable salt thereof. ru.

[0350] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and N-(5-(4 -(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrim Zin-2-yl)methyl)-3-methoxyphenyl)piperazin-1-yl)-5-oxy A composition comprising sopentyl tetradecanamide or a pharmaceutically acceptable salt thereof. provide.

[0351] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and N-(5-(4 -(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrim Zin-2-yl)methyl)-3-methoxyphenyl)piperazin-1-yl)-5-oxy The present invention provides a composition comprising sopentyl oleamide or a pharmaceutically acceptable salt thereof. .

[0352] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and (9Z,12Z )-N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[ 4,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1 -yl)-5-oxopentyl)octadeca-9,12-dienamide, or its pharmaceutical The present invention provides a composition comprising a generally acceptable salt.

[0353] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and N-(5-(4 -(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrim Zin-2-yl(methyl)-3-methoxyphenyl)-1,4-diazepan-1-yl) A composition comprising (-5-oxopentyl) stearamide, or a pharmaceutically acceptable salt thereof. To provide goods.

[0354] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and N-(5-(4 -(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrim Zin-2-yl)methyl)-3-methoxyphenyl)piperidine-1-yl)-5-oxy The present invention provides a composition comprising sopentyl stearamide or a pharmaceutically acceptable salt thereof. ru.

[0355] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and N-(5-(3 -(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrim Zin-2-yl)methyl)-3-methoxyphenyl)azetidine-1-yl)-5-oxy The present invention provides a composition comprising sopentyl stearamide or a pharmaceutically acceptable salt thereof. ru.

[0356] In some embodiments, the present invention comprises one or more Streptococcus pneumoniae antigens and 1-(4-(( 5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidine-2-i (L)methyl-3-methoxyphenyl-N-(3-stearamidopropyl)piperidine The present invention provides a composition comprising -4-carboxamide or a pharmaceutically acceptable salt thereof.

[0357] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and (1s,3s) -3-(2-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Iyl)-2-oxoethyl)-N-octadecylcyclobutan-1-carboxamide, The present invention provides a composition comprising a pharmaceutically acceptable salt thereof.

[0358] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and (1s,3s) -3-(2-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Iyl)-2-oxoethyl)-N-hexadecylcyclobutan-1-carboxamide, The present invention provides a composition comprising a pharmaceutically acceptable salt thereof.

[0359] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and N-(3-(4 -(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrim Zin-2-yl)methyl)-3-methoxyphenyl)piperazin-1-yl)-3-oxy The present invention provides a composition comprising sopropyl stearamide or a pharmaceutically acceptable salt thereof. ru.

[0360] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and N-(7-(4 -(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrim Zin-2-yl)methyl)-3-methoxyphenyl)piperazin-1-yl)-7-oxy The present invention provides a composition comprising soheptyl stearamide or a pharmaceutically acceptable salt thereof. ru.

[0361] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and N-(3-(2 -(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d] Pyrimidine-2-yl)methyl)-3-methoxyphenyl)piperazine-1-yl)-2 -Oxoethyl)cyclobutyl)stearamide, or a pharmaceutically acceptable salt thereof, The present invention provides a composition containing the following:

[0362] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and N-(5-(4 -(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrim Zin-2-yl)methyl)-3-methoxyphenyl)piperazin-1-yl)-4,4- Dimethyl-5-oxopentyl stearamide, or a pharmaceutically acceptable salt thereof, The present invention provides a composition containing the following:

[0363] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and N-(6-(4 -(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrim Zin-2-yl)methyl)-3-methoxyphenyl)piperazin-1-yl)-2-methyl (Lu-6-oxohexane-2-yl) stearamide, or a pharmaceutically acceptable salt thereof The present invention provides a composition containing ,

[0364] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and 1-(4-(4 -((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidine- 2-Il)methyl)-3-methoxyphenyl)piperazine-1-Il)-5-(octade A composition comprising siloxy)pentan-1-one or a pharmaceutically acceptable salt thereof. provide.

[0365] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and 1-(4-(4 -((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidine- 2-Il)methyl)-3-methoxyphenyl)piperazine-1-Il)-5-(octade A composition comprising sylaminopentan-1-one or a pharmaceutically acceptable salt thereof. provide.

[0366] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and N-(5-(4 -(4-((5-amino-7-(butylamino)-3-methyl-2H-pyrazolo[4,3 -d] Pyrimidine-2-yl)methyl)-3-methoxyphenyl)piperazine-1-yl A combination comprising )-5-oxopentyl) stearamide, or a pharmaceutically acceptable salt thereof. To provide finished products.

[0367] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and (9Z,12Z )-N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4, 3-d]Pyrimidine-2-yl(methyl)-3,5-dimethoxybenzyl(methyl) Mino-butyl octadeca-9,12-dienamide, or its pharmaceutically acceptable salt. The present invention provides a composition containing the following:

[0368] In some embodiments, the present invention comprises one or more Streptococcus pneumoniae antigens and N-(4-(( 4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidine -2-yl(methyl)-3,5-dimethoxybenzyl)(methyl)amino(butyl)tetra The present invention provides a composition comprising ladecanamide or a pharmaceutically acceptable salt thereof.

[0369] In some embodiments, the present invention comprises one or more Streptococcus pneumoniae antigens and N-(4-(( 4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidine (-2-yl)methyl)-3,5-dimethoxybenzyl)(methyl)amino)butyl)ole The present invention provides a composition comprising an amide, or a pharmaceutically acceptable salt thereof.

[0370] In some embodiments, the present invention comprises one or more Streptococcus pneumoniae antigens and N-(4-(( 4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidine -2-yl(methyl)-3,5-dimethoxybenzyl)(methyl)amino(butyl) sterol The present invention provides a composition comprising aramid or a pharmaceutically acceptable salt thereof.

[0371] In some embodiments, the present invention comprises one or more Streptococcus pneumoniae antigens and N-(4-(( 4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidine -2-yl)methyl)-3,5-dimethoxybenzyl)(methyl)amino)-4-oxo The present invention provides a composition comprising butyl stearamide or a pharmaceutically acceptable salt thereof.

[0372] In some embodiments, the present invention comprises one or more Streptococcus pneumoniae antigens and (6Z,9Z, 28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl (4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d] Pyrimidine-2-yl(methyl)-3,5-dimethoxybenzyl(methyl)amino(b) The present invention provides a composition comprising a chlorocarbamate or a pharmaceutically acceptable salt thereof.

[0373] In some embodiments, the present invention comprises one or more Streptococcus pneumoniae antigens and 4-(4-(( 5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidine-2-i (L)methyl-3-methoxyphenyl-N-(3-stearamidopropyl)piperazine The present invention provides a composition comprising -1-carboxamide or a pharmaceutically acceptable salt thereof.

[0374] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and 3-stearamix Dopropyl 4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3 -d] Pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1-cal The present invention provides a composition comprising a benzene ring or a pharmaceutically acceptable salt thereof.

[0375] In some embodiments, the present invention provides one or more Streptococcus pneumoniae antigens and N-(5-(4 -(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrim Zin-2-yl)methyl)-3-methoxyphenyl)piperazin-1-yl)-6,6, Contains 6-trifluorohexyl) stearamide, or a pharmaceutically acceptable salt thereof. A composition is provided.

[0376] In some embodiments, the present invention comprises one or more Streptococcus pneumoniae antigens and N-(4-(( 4-((7-(butylamino)-5-hydroxy-2H-pyrazolo[4,3-d]pyrim Zin-2-yl(methyl)-3,5-dimethoxybenzyl(methyl)amino(butyl) The present invention provides a composition comprising stearamide or a pharmaceutically acceptable salt thereof.

[0377] In some embodiments, the present invention comprises one or more Streptococcus pneumoniae antigens and (6Z,9Z, 28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl (5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3- d) Pyrimidine-2-yl)methyl)-3-methoxyphenyl)piperazine-1-yl) A composition comprising -5-oxopentyl)carbamate or a pharmaceutically acceptable salt thereof. To provide goods.

[0378] Adjuvant Adjuvant-based approaches enhance vaccine immunogenicity, particularly against infectious diseases. Addressing unmet medical needs in highly sensitive populations. It is being investigated to help with (i.e., immunocompromised, elderly, or child populations) ).

[0379] For example, the incidence of invasive pneumococcal disease (IPD) is affected by the pneumococcal conjugate vaccine. Although the incidence decreased dramatically in both children and adults after the introduction of the vaccine, the sustained vaccine serotype still... Residual diseases caused by this remain. Furthermore, serotype-specific immune responses vary, The introduction of PCV with extended titers resulted in an overall reduction in serotype-specific immune responses. Adjuvant-based strategies to enhance the immunogenicity of PCV are effective against difficult serotypes. To enhance the effectiveness of vaccines, provide a more sustained immune response, or adjust the medication schedule This could make shortening the process possible.

[0380] Preclinical data suggest that TLR7 / 8 agonists can increase the immunogenicity of PCV. This indicates that Dowling et al. found that PCV13 alone (PCV13 is PCV13+TLR7 / 8 agonist compared to (containing alum adjuvant) Binding antibody titers in neonatal and infant rhesus monkeys immunized with 3M-052 Acceleration and enhancement of serotype-specific antibody responses, including both functional opsonization and phagocytic killing. Both have been reported. Adding TLR7 / 8 agonists to PCV13 also shows signs of infant red hair. In sieves, Th1 polarized CRM197-specific CD4 T cells and juvenile streptococcus pneumoniae Induces specific B cells and stimulates type II IFN and T cells in vitro after stimulation of human neonatal umbilical cord blood. Enhanced H1 polarization cytokine production (JCI Insight 2017:e910) 20).

[0381] Adjuvant preparations This disclosure relates to 1) one or more of the compounds of the present invention, or (one or more) thereof pharmaceutically It contains 1) acceptable salts, 2) SPAN-85, 3) PS-20, and 4) squalene. We provide adjuvant formulations.

[0382] This disclosure relates to 1) the compound of the present invention, or a pharmaceutically acceptable salt thereof, and 2) SPAN- Adjuvants containing 85, 3) PS-20 or PS-80, and 4) Squalene. We provide the agent.

[0383] This disclosure relates to 1) the compound of the present invention, or a pharmaceutically acceptable salt thereof, and 2) SPAN- The present invention provides an adjuvant formulation comprising 85, 3) PS-20, and 4) squalene.

[0384] General method for preparing SNE preparations Generally, SNEs are formed, for example, by first combining and mixing the components together. It is possible. After mixing and blending, add aqueous buffer and mix with the initial compound components. , forming a blended emulsion mixture. In some embodiments, the blended The emulsion components are first subjected to coarse homogenization, followed by fine homogenization. The resulting formulation is then subjected to a final filtration step and stored at 4°C. The solution contains one or more compounds. One or more sorbitan-based surfactants (e.g., PS-20; PS-80; SPAN-85) ), and may include one or more terpenes (e.g., squalene) in a specific molar ratio.

[0385] Alternatively, the process for preparing the SNE of the present invention consists of four main steps: 1) Functional component 1) Preparation of a solution with a component mixture containing non-functional components and an aqueous buffer, 2) by separate flow mixing The process consists of 3) SNE formation, 4) ultrafiltration, and 5) filtration.

[0386] Generally, the ingredients are sterilized and filtered, then dissolved in ethanol before forming a mixture. A aqueous buffer solution is also prepared. The mixture and buffer solution stream are then placed in a T tube or Y tube. Combine using a mixer, then dilute immediately after the outlet and mix with aqueous buffer to form an intermediate solution for SNE. The body is formed. Next, the SNE intermediate is subjected to ultrafiltration or dialysis to concentrate the material. In both cases, the material is replaced with a suitable buffer solution to remove residual ethanol. Diafil tray After the initial stage, there is a final concentration process that is carried out to achieve the final target concentration. Next, SNE Filter the bulk material using a sterile filter.

[0387] SNE preparations In some embodiments, SNE is 1) about 0-75 mol% of formulas I, Ia, II, I Compounds of Ia, III, IIIa, IV, and IVa, or their pharmaceutically acceptable salts. 2) SPAN-85 at approximately 0-30 mol%, and 3) PS-20 at approximately 0-30 mol%. Alternatively, a formulation is provided that includes PS-80 and 4) 25-85 mol% squalene. .

[0388] In some embodiments, SNE is 1) about 0-50 mol% of formulas I, Ia, II, I Compounds of Ia, III, IIIa, IV, and IVa, or their pharmaceutically acceptable salts. 2) SPAN-85 at approximately 0-10 mol%, and 3) PS-20 at approximately 0-10 mol%. Alternatively, a formulation is provided containing PS-80 and 4) approximately 50-80 mol% squalene. ru.

[0389] In some embodiments, SNE is 1) about 0-24 mol% of formulas I, Ia, II, I Compounds of Ia, III, IIIa, IV, and IVa, or their pharmaceutically acceptable salts. 2) SPAN-85 at approximately 1-8 mol%, and 3) PS-20 at approximately 1-8 mol%. A formulation is provided that contains PS-80 and 4) approximately 60-75 mol% squalene.

[0390] In some embodiments, SNE is 1) about 10-14 mol% of formulas I, Ia, II, Compounds of type IIa, III, IIIa, IV, and IVa, or their pharmaceutically acceptable forms. 1) Salt, 2) approximately 1-4 mol% SPAN-85, and 3) approximately 1-4 mol% PS-20 A formulation is provided that contains PS-80 and 4) approximately 50-80 mol% squalene. .

[0391] In some embodiments, SNE is 1) about 30-65 mol% of formulas I, Ia, II, Compounds of type IIa, III, IIIa, IV, and IVa, or their pharmaceutically acceptable forms. 1) Salt, 2) approximately 5-30 mol% SPAN-85, and 3) approximately 0.5-4 mol% PS- A formulation is provided that contains 20 or PS-80 and 4) approximately 10-40 mol% squalene. It will be done.

[0392] In some embodiments, SNE is 1) about 55-65 mol% of formulas I, Ia, II, Compounds of type IIa, III, IIIa, IV, and IVa, or their pharmaceutically acceptable forms. 1) Salt, 2) approximately 5-15 mol% SPAN-85, and 3) approximately 1-2.5 mol% PS- A formulation is provided that contains 20 or PS-80 and 4) approximately 25-35 mol% squalene. It will be done.

[0393] In some embodiments, SNE is 1) about 13-45 mol% of formulas I, Ia, II, Compounds of type IIa, III, IIIa, IV, and IVa, or their pharmaceutically acceptable forms. 1) Salt, 2) approximately 2-4 mol% SPAN-85, and 3) approximately 1.5-3 mol% PS-2 A formulation is provided containing 0 or PS-80 and 4) approximately 50-82 mol% squalene. It can be done.

[0394] In some embodiments, SNE is 1) about 13-14 mol% of formulas I, Ia, II, Compounds of type IIa, III, IIIa, IV, and IVa, or their pharmaceutically acceptable forms. 1) Salt, 2) about 1-2 mol% SPAN-85, and 3) about 1-2 mol% PS-20 A formulation is provided that contains PS-80 and 4) approximately 79-81 mol% squalene. .

[0395] In some embodiments, SNE is approximately 1-60 mol% of formulas I, Ia, II, and IIa. , compounds of III, IIIa, IV and IVa, or pharmaceutically acceptable salts thereof, 2) Approximately 1-4 mol% of SPAN-85, and 3) Approximately 1-4 mol% of PS-20 or P A formulation is provided that contains S-80 and 4) approximately 32-97 mol% squalene.

[0396] In some embodiments, SNE is 1) about 0-45 mol% of formulas I, Ia, II, I Compounds of Ia, III, IIIa, IV, and IVa, or their pharmaceutically acceptable salts. 2) Approximately 1-10 mol% nonionic surfactant and 3) Approximately 50-85 mol% A formulation containing qualene is provided. In one embodiment of this model, a nonionic surfactant The agent contains a mixture of SPAN-85 and PS-20 or PS-80.

[0397] In some embodiments, SNE is 1) about 0-75 mol% of formulas I, Ia, II, I Compounds of Ia, III, IIIa, IV, and IVa, or their pharmaceutically acceptable salts. 2) SPAN-85 at approximately 0-30 mol%, and 3) PS-20 at approximately 0-30 mol%. A formulation containing 4) 25-85 mol% squalene is provided.

[0398] In some embodiments, SNE is 1) about 0-50 mol% of formulas I, Ia, II, I Compounds of Ia, III, IIIa, IV, and IVa, or their pharmaceutically acceptable salts. 2) SPAN-85 at approximately 0-10 mol%, and 3) PS-20 at approximately 0-10 mol%. 4) A formulation containing approximately 50-80 mol% squalene is provided.

[0399] In some embodiments, SNE is 1) about 0-24 mol% of formulas I, Ia, II, I Compounds of Ia, III, IIIa, IV, and IVa, or their pharmaceutically acceptable salts. 2) SPAN-85 at approximately 1-8 mol%, and 3) PS-20 at approximately 1-8 mol%, 4) A formulation containing approximately 60-75 mol% squalene is provided.

[0400] In some embodiments, SNE is 1) about 10-14 mol% of formulas I, Ia, II, Compounds of type IIa, III, IIIa, IV, and IVa, or their pharmaceutically acceptable forms. 1) Salt, 2) about 1-4 mol% SPAN-85, and 3) about 1-4 mol% PS-20 4) A formulation containing approximately 50-80 mol% squalene is provided.

[0401] In some embodiments, SNE is 1) about 30-65 mol% of formulas I, Ia, II, Compounds of type IIa, III, IIIa, IV, and IVa, or their pharmaceutically acceptable forms. 1) Salt, 2) approximately 5-30 mol% SPAN-85, and 3) approximately 0.5-4 mol% PS- A formulation is provided that contains 20 and 4) approximately 10-40 mol% squalene.

[0402] In some embodiments, SNE is 1) about 55-65 mol% of formulas I, Ia, II, Compounds of type IIa, III, IIIa, IV, and IVa, or their pharmaceutically acceptable forms. 1) Salt, 2) approximately 5-15 mol% SPAN-85, and 3) approximately 1-2.5 mol% PS- A formulation is provided that contains 20 and 4) approximately 25-35 mol% squalene.

[0403] In some embodiments, SNE is 1) about 13-45 mol% of formulas I, Ia, II, Compounds of type IIa, III, IIIa, IV, and IVa, or their pharmaceutically acceptable forms. 1) Salt, 2) approximately 2-4 mol% SPAN-85, and 3) approximately 1.5-3 mol% PS-2 A formulation is provided that contains 0 and 4) approximately 50-82 mol% squalene.

[0404] In some embodiments, SNE is 1) about 13-14 mol% of formulas I, Ia, II, Compounds of type IIa, III, IIIa, IV, and IVa, or their pharmaceutically acceptable forms. 1) Salt, 2) about 1-2 mol% SPAN-85, and 3) about 1-2 mol% PS-20 4) A formulation containing approximately 79-81 mol% squalene is provided.

[0405] In some embodiments, SNE is approximately 1-60 mol% of formulas I, Ia, II, and IIa. , compounds of III, IIIa, IV and IVa, or pharmaceutically acceptable salts thereof, 2) SPAN-85 at approximately 1-4 mol%, 3) PS-20 at approximately 1-4 mol%, and 4) A formulation containing approximately 32-97 mol% squalene is provided.

[0406] In some embodiments, SNE is 1) about 0-45 mol% of formulas I, Ia, II, I Compounds of Ia, III, IIIa, IV, and IVa, or their pharmaceutically acceptable salts. 2) Approximately 1-10 mol% nonionic surfactant and 3) Approximately 50-85 mol% A formulation containing qualene is provided. In one embodiment of this model, a nonionic surfactant The agent contains a mixture of SPAN-85 and PS-20.

[0407] In some embodiments, the formulation provided above is (N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[ 4,3-d]pyrimidine-2-yl(methyl)-3,5-dimethoxyphenyl)piperazi (-1-yl)-5-oxopentyl) stearamide (compound A-1), (S)-N-(5-(4-(4-((5-amino-7-((1-hydroxypentane- 2-yl)amino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)- 3,5-Dimethoxyphenyl)piperazin-1-yl)-5-oxopentyl)stear Mido (compound A-2), (S)-1-(4-(4-((5-amino-7-((1-hydroxypentan-2-i (Lu)amino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3,5 -Dimethoxyphenyl)piperazine-1-yl)octadecane-1-one (compound A-3) ), N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Iyl)-5-oxopentyl)stearamide (compound B-1), N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Iyl)-5-oxopentyl)tetradecanamide (compound B-2), N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- Iyl-5-oxopentyl)oleamide (compound B-3), (9Z,12Z)-N-(5-(4-(4-((5-amino-7-(butylamino)- 2H-Pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3-methoxyphenyl )piperazine-1-yl)-5-oxopentyl)octadeca-9,12-dienamide (Compound B-4), N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 [3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)-1,4-diaze Pan-1-yl)-5-oxopentyl) stearamide (compound B-5), N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperidine-1- (Iyl)-5-oxopentyl)stearamide (compound B-6), N-(5-(3-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)azetidine-1- (Iyl)-5-oxopentyl)stearamide (compound B-7), 1-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]py Limidine-2-yl(methyl)-3-methoxyphenyl)-N-(3-stearamidopro Pill) Piperidine-4-carboxamide (compound B-8), (1s,3s)-3-(2-(4-(4-((5-amino-7-(butylamino)-2 H-Pyrazolo[4,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl) Piperazine-1-yl)-2-oxoethyl)-N-octadecylcyclobutane-1-ca Ruboxamide (compound B-9), (1s,3s)-3-(2-(4-(4-((5-amino-7-(butylamino)-2 H-Pyrazolo[4,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl) Piperazine-1-yl)-2-oxoethyl)-N-hexadecylcyclobutane-1- Ruboxamide (compound B-10), N-(3-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Iyl)-3-oxopropyl) stearamide (compound B-11), N-(7-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Iyl)-7-oxoheptyl)stearamide (compound B-12), N-(3-(2-(4-(4-((5-amino-7-(butylamino)-2H-pyrazo Ro[4,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl(piperazine) -1-yl)-2-oxoethyl)cyclobutyl)stearamide (compound B-13), N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Iyl)-4,4-dimethyl-5-oxopentyl)stearamide (compound B-14), N-(6-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Iyl)-2-methyl-6-oxohexane-2-yl)stearamide (compound B-15) , 1-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3- d) Pyrimidine-2-yl)methyl)-3-methoxyphenyl)piperazine-1-yl) -5-(octadecyloxy)pentan-1-one (compound B-16), 1-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3- d) Pyrimidine-2-yl)methyl)-3-methoxyphenyl)piperazine-1-yl) -5-(octadecylamino)pentan-1-one (compound B-17), N-(5-(4-(4-((5-amino-7-(butylamino)-3-methyl-2H- Pyrazolo[4,3-d]pyrimidine-2-yl)methyl)3-methoxyphenyl)pipette Radin-1-yl)-5-oxopentyl) stearamide (compound B-18), (9Z,12Z)-N-(4-((4-((5-amino-7-(butylamino)-2H -Pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3,5-dimethoxybendi (Methyl)aminobutyl)octadeca-9,12-dienamide (compound C-1) , N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3 -d]pyrimidine-2-yl(methyl)-3,5-dimethoxybenzyl(methyl)amine (N)Butyl)tetradecanamide (compound C-2), N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3 -d]pyrimidine-2-yl(methyl)-3,5-dimethoxybenzyl(methyl)amine (N)Butyl)oleamide (compound C-3), N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3 -d]pyrimidine-2-yl(methyl)-3,5-dimethoxybenzyl(methyl)amine (N)Butyl)Stearamide (compound C-4), N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3 -d]pyrimidine-2-yl(methyl)-3,5-dimethoxybenzyl(methyl)amine (-4-oxobutyl)stearamide (compound C-5), (6Z,9Z,28Z,31Z)-Heptatriaconta-6,9,28,31-Tetra En-19-yl(4-((4-((5-amino-7-(butylamino)-2H-pyrazo Ro[4,3-d]pyrimidine-2-yl(methyl)-3,5-dimethoxybenzyl)(Me Chill-amino-butyl carbamate (compound D-1), 4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]py Limidine-2-yl(methyl)-3-methoxyphenyl)-N-(3-stearamidopro Pill) Piperazine-1-carboxamide (compound D-2), 3-Stearamidopropyl 4-(4-((5-Amino-7-(butylamino)-2H- Pyrazolo[4,3-d]pyrimidine-2-yl)methyl)3-methoxyphenyl)pipette Radin-1-carboxylate (compound D-3), N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Iyl)-6,6,6-trifluorohexyl)stearamide (compound D-4), N-(4-((4-((7-(butylamino)-5-hydroxy-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3,5-dimethoxybenzyl(methyl) Amino)butyl)stearamide (compound D-5), and (6Z,9Z,28Z,31Z)-Heptatriaconta-6,9,28,31-Tetra En-19-yl(5-(4-(4-((5-amino-7-(butylamino)-2H-p Lazolo[4,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl(piper) Zin-1-yl)-5-oxopentyl)carbamate (compound D-6), It comprises a specific compound selected from, or a pharmaceutically acceptable salt thereof.

[0408] In some embodiments of the present invention, SNE is a surfactant, a mixture of surfactants, phosphorus Selected from lipids, terpenes, terpenoids, triterpenes, or combinations thereof. A formulation is provided that further contains one or more additional ingredients.

[0409] In some embodiments of the present invention, the surfactant is polyoxyethylene sorbita Ester surfactants (commonly called Tween), especially PS-20 and PS-8 0; Linear EO / PO block copolymers, etc., sold under the trade name DOWFAX (trademark) Ethylene oxide (EO), propylene oxide (PO), and / or buty Rene oxide (BO) copolymer; repeated ethoxy(oxy-1,2-ethanediyl) group The number may vary, octoxynol-9 (Triton X-100, or t-octoxy Luphenoxypolyethoxyethanol is particularly interesting, as is octoxyl (octyl). Phenoxy(Polyethoxyethanol)(IGEPALCA-630 / NP-40); Noni Luphenol ethoxylates, e.g., Tergitol® NP series; lauryl , cetyl, stearyl, and oleyl alcohol (known as Brij surfactants) Polyoxyethylene fatty ethers derived from these, such as triethylene glycol monolauamic acid, are also derived. Lil ether (Brij30); sorbitan trioleate (Span-85, Twee n-85, or [2-[(2R,3S,4R)-4-hydroxy-3-[(Z)-oc Tadeca-9-enoyl]oxyoxolan-2-yl]-2-[(Z)-octadeca-9 -Enoyl]oxyethyl](Z)-octadeca-9-enoate) and sorbitan Examples include sorbitan esters such as nolaurate (generally known as SPAN), This is not limited to these.

[0410] In some embodiments of the present invention, a mixture of surfactants is used, for example, PS-20 / Span 85 mixture is used. Polyoxyethylene sorbitan monooleate (PS-80) Polyoxyethylene sorbitan esters such as t-octylphenoxypolyethoxy Combinations with octoxyl, such as ethanol (Triton X-100), are also suitable. Another useful combination is laureth-9 + polyoxyethylene sorbitan ester. and / or containing octoxynol.

[0411] In some embodiments of the present invention, the amount of surfactant or emulsifier is polyoxyethylene Insorbitan ester (such as PS-20) 0.01-10 mol%, especially about 1-4 mol% Octyl- or nonylphenoxypolyoxyethanol (Triton X-100 (or other detergents in the Triton series, etc.) 0.001~10 mol%, especially about 1~ 4 mol%; w / v, especially 0.01~0.1% w / v; polyoxyethylene ether ( (e.g., Ureth 9) 0.1-20 mol%, preferably 0.5-10 mol%, especially 1-4 m This is ol% or approximately 10% by mass.

[0412] In some embodiments of the present invention, the phospholipid is phosphatidylcholine (PC), Phatidylethanolamine (PE) and phosphatidylglycerol (PG), Sphatidylserine (PS), phosphatidylinositol (PI), phosphatidic acid (Phosphatidic acid) (PA), dipalmitoylphosphatidylcholine, monoacyl- Phosphatidylcholine (LysoPC), 1-Palmitoyl-2-Oleoyl-sn-Glycerides Ro-3-phosphocholine (POPC), N-acyl-PE, phosphoinositide, and ho Selected from natural phospholipids containing phosphorus sphingolipids. Phosphosphingolipid derivatives include Phatidic acid (DMPA, DPPA, DSPA), phosphatidylcholine (DDPC, D LPC, DMPC, DPPC, DSPC, DOPC, POPC, DEPC), phosphatidyl Diglycerol (DMPG, DPPG, DSPG, POPG), phosphatidyl ethanol Dolamines (DMPE, DPPE, DSPE DOPE), phosphatidylserine (DO Examples include PS). Fatty acids include C14:0, palmitic acid (C16:0), and ste Alic acid (C18:0), oleic acid (C18:1), linoleic acid (C18:2), linoleic acid Lentic acid (C18:3), and arachidonic acid (C20:4), C20:0, C22:0, Ethicine is also mentioned. In a particular embodiment of the present invention, the phospholipid is phosphor Adidylserine, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSP C) 1,2-Dipalmitoleoyl-sn-glycero-3-phosphocholine, 1,2-di Myristoyl-sn-glycero-3-phosphocholine (DMPC), dilauroyl phosphatidyl Tidylcholine (DLPC), 1,2-dieicosenoyl-sn-glycero-3-phosphoco Phosphorus, or 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) be.

[0413] In some embodiments of the present invention, terpenes are geraniol, terpenol, limonene Selected from monoterpenes such as ammonium compounds, myrcene, linalool, or pinene. In this embodiment, the formulation is humulene, farnesene, or farnesol; Cafest Diterpenes such as squalene, squalene, sembrene, or taxadiene; or triterpenes such as squalane; acyclic lycopene, monocyclic gamma-carotene, or tetraterpenes such as bicyclic alpha- and beta-carotenes; polyterpenes also It contains sesquiterpenes, which are composed of norisoprenoids.

[0414] Pneumococcal vaccine composition Pneumococcal vaccines or compositions are well known (e.g., PNEUMOVAX (registered trademark)). (Merck & Co., Inc. (Loway, New Jersey, USA)) Pneumonia A cocci conjugate vaccine or composition has been previously disclosed. International Publication No. 201 Issue 1 / 100151, International Publication No. 2019 / 139692, and International Publication No. 2020 Please refer to issue / 131763.

[0415] Exemplary bacterial capsular polysaccharides derived from Streptococcus pneumoniae include, in particular, 1, 2, 3, 4, 5, 6A, 6B, 6C, 7C, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15A, 1 5B, 15C, 16F, 17F, 18C, 19A, 19F, 20 (20A and 20B) Blood types 22F, 23A, 23B, 23F, 24F, 33F, 35B, 35F, or 38 It is a pure style.

[0416] General method for preparing capsule polysaccharides Bacterial capsular polysaccharides, particularly those used as antigens, are suitable for use in the present invention. They can be easily identified by methods for identifying immunogenic and / or antigenic polysaccharides. Yes, it is possible. Exemplary bacterial capsular polysaccharides derived from Streptococcus pneumoniae include, in particular, 1, 2, 3, 4, 5. 6A, 6B, 6C, 7C, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15 A, 15B, 15C, 16F, 17F, 18C, 19A, 19F, 20(20A and 2 0B), 22F, 23A, 23B, 23F, 24F, 33F, 35B, 35F, or 3 It is serotype 8.

[0417] When used herein, it refers to de-O-acetylated serotype 15B (DeOAc15B) pneumonia. Cocci polysaccharides are substantially equivalent to those of serotype 15C pneumococcus polysaccharides and are substantially identical in NMR spectrum. It has a vector (data not shown). When used herein, deoxyacetylated blood Clear type 15B pneumococcus polysaccharide and serotype 15C pneumococcus polysaccharide each exist in the range of 0-5%, This ranges from 0 to 4%, or from 0 to 3%, or from 0 to 2%, or from 0 to 1%. Having an O-acetyl content in the range of 0-0.5% or 0-0.1% It either contains or does not contain O-acetyl. Spencer BL, et al. According to reports, pneumococcal polysaccharide 15C may be slightly O-acetylated (S pencer,BLet al.,Clin.Vac.Immuno.(2017) 24(8):1-13). Therefore, embodiments of the polyvalent immunogenic compositions described herein In either case, de-O-acetylated serotype 15B (DeOA) is used instead of serotype 15C. c15B) can be used. The de-O-acetylation process is, for example, Raja m et al.,Clinical and Vaccine Immunology As described in 2007, 14(9):1223-1227, public in the art It is knowledge.

[0418] Polysaccharides can be purified by known techniques. However, this invention relates to the purification of polysaccharides from natural sources. Not limited to purified polysaccharides, polysaccharides can be synthesized by other methods such as total synthesis or partial synthesis. Capsular polysaccharides derived from Streptococcus pneumoniae may be obtained by standard techniques known to those skilled in the art. It can be prepared. For example, polysaccharides can be isolated from bacteria by known methods. It can be made to a certain size (for example, European Patent No. 497524 specification and (See also European Patent No. 497525) the homogenizer is used to achieve the same result The method is preferably one of chloroformation or chemical hydrolysis. The corresponding Streptococcus pneumoniae strain may be grown in a soybean-based medium. Then, the individual polysaccharides It may be purified through standard processes including centrifugation, precipitation, and ultrafiltration. Example For example, U.S. Patent Application Publication No. 2008 / 0286838 and U.S. Patent Application Publication No. 5,84 See Specification No. 7,112. Polysaccharides are used to reduce viscosity, and / or The size is designed to improve filterability and lot-to-lot consistency of the subsequent conjugate product. It is possible to decide.

[0419] Purified polysaccharides have functional groups that can react with carrier proteins using standard techniques. It can be chemically activated for introduction. Chemical activation of polysaccharides and subsequent carrier Conjugation to body proteins is described in U.S. Patent No. 4,365,170, and the same patent. The specifications described in Specification No. 4,673,574 and Specification No. 4,902,506 The concise method achieved by this means involves using sodium periodate to remove pneumococcal polysaccharides, and sodium periodate. It reacts with a periodic acid-based oxidizing agent such as lium or periodic acid, and the adjacent hydroxyl This leads to oxidative cleavage of the aldehyde group, generating a reactive aldehyde group. Periodates (for example, A suitable molar equivalent of sodium periodate, sodium metaperiodate, etc. is 0 0.05-0.5 molar equivalents (molar ratio of periodate to polysaccharide repeat units) or 0.1-0.5 Molar equivalents are one example. The periodate reaction involves the reaction of a reactive hydroxyl group with sodium periodate. Diol conformations (e.g., acyclic diols, cis-diols) control the accessibility of um. Depending on the transdiol, the time may vary from 30 minutes to 24 hours.

[0420] The term "periodate" includes both periodate and periodic acid, and this usage The word also refers to metaperiodate (IO). 4- ) and orthoperiodate (IO 6- Both of ) It includes various salts of periodate (e.g., sodium periodate and potassium periodate) Contains (N). Capsular polysaccharides are used in the presence of metaperiodate or sodium periodate (N). It can be oxidized in the presence of aIO4). Furthermore, the capsular polysaccharide can be oxidized in the presence of orthoperiodate. Alternatively, it can be oxidized in the presence of periodic acid.

[0421] Purified polysaccharides can also be linked to linkers. Once activated or linked to linkers Once linked, each capsule polysaccharide is separately conjugated to a carrier protein to form a complex carbohydrate. Polysaccharide conjugates can be formed. These conjugates can be prepared by known bonding techniques.

[0422] Polysaccharides are bonded to a linker, and the free end of the linker is an ester group, resulting in a polysaccharide-linker. An intermediate can be formed. Therefore, the linker has at least one terminal that is E It is a linker, which is a tel group. The other end reacts with a polysaccharide to form a polysaccharide-linker intermediate. They are selected to be able to form a body.

[0423] Polysaccharides can be bonded to a linker using the primary amine groups within the polysaccharide. Linkers typically have ester groups at both ends. This results in a nucleophilic acyl configuration. By conversion, one of the ester groups reacts with a primary amine group in the polysaccharide. Bonding can occur. In this reaction, the polysaccharide is bonded to the linker via an amide bond. This yields a polysaccharide-linker intermediate. Therefore, the linker is formed when the primary amine group in the polysaccharide A first ester group for reacting with and a primary amine group in the support molecule for reacting with It is a bifunctional linker that provides a second ester group. A typical linker is adipic acid. It is N-hydroxysuccinimide diester (SIDEA).

[0424] The bond is also used indirectly, i.e., to derivatize the polysaccharide before bonding to the linker. This can also be done using additional linkers.

[0425] Polysaccharides can be linked to additional linkers using carbonyl groups at the reducing end of the polysaccharide. Yes, it is possible. This bond is formed in two steps: (a1) the carbonyl group reacts with an additional linker. The process includes (a2) reacting the free ends of the additional linker with the linker. In these embodiments, the additional linker typically has primary amine groups at both ends. This allows one of the primary amine groups to be removed from the polysaccharide by reductive amination. Reacting with the carbon group makes it possible to carry out step (a1). A primary amine group that is reactive with the hydroxyl group is used. A hydrazide group or hydroxyl amine group is used. The no group is preferred. The same primary amine group typically allows for polysaccharide (Ps)-Ps bonding. An additional linker is present at both ends, enabling the relationship between the CN bond and the polysaccharide. The polysaccharide is linked to an additional linker via this process, resulting in an additional linker intermediate.

[0426] Polysaccharides are bonded to additional linkers using different groups in the polysaccharide, particularly carboxyl groups. This bond can be formed in two steps: (a1) reacting the group with an additional linker. This includes (a2) a step of reacting the free ends of the additional linker with the linker. In this case, the additional linker typically has primary amine groups at both ends, thereby E DAC activation causes one of the primary amine groups to react with a carboxyl group in the polysaccharide. This makes it possible to perform step (a1). EDAC-activated carboxymethyl A primary amine group that is reactive with the syl group is used. A hydrazide group is preferred. Primary amine groups are typically present at both ends of the additional linker. This reaction is multi A polysaccharide in which sugar is linked to an additional linker via an amide bond - an additional linker intermediate To drip.

[0427] Carrier protein In certain embodiments of the present invention, CRM197 is used as the carrier protein. M197 is a non-toxic variant (i.e., toxoid) of diphtheria toxin. CRM1 97 is Corynebacterium grown in a culture medium based on caustic amino acids and yeast extracts. • Diphtheria (Corynebacterium diphtheria) strain C7(β1 It can be isolated from the culture of 97). Furthermore, CRM197 is U.S. Patent No. 5,614,3 It can be prepared by recombination according to the method described in Specification No. 82. Typically, C RM 197 This involves ultrafiltration, ammonium sulfate precipitation, and ion exchange chromatography. It is purified by a combination of. In some embodiments, CRM197 is Pfen ex Expression Technology(TM)(Pfenex Inc. (San Diego, California) used Pseudomonas fluorescein ( It is prepared in Pseudomonas fluorescens.

[0428] Other suitable carrier proteins include DT (diphtheria toxoid) and TT (tetanus toxoid). (xoid) or fragment C of TT, pertussis toxoid, cholera toxoid (e.g., international public (As described in Publication No. 2004 / 083251), Escherichia coli LT, Escherichia coli ST, and Green Examples include additional inactivated bacterial toxins such as exotoxin A derived from pyogenes. Bacterial outer membrane proteins, For example, outer membrane complex c (OMPC), porin, transferrin-binding protein, pneumococcus Surface protein A (PspA; see International Publication No. 02 / 091998), surface of Streptococcus pneumoniae Adhesin protein (PsaA), C5a peptide derived from Group A or Group B Streptococcus. Ze, or Haemophilus influenzae protein D, Streptococcus pneumoniae pneumocysin (Kuo et al. l., 1995, Infect Immun 63;2706-13), for example, some PLY detoxified in a specific format, e.g., dPLY-GMBS (International Publication No. 04 / 081515) (See also) or containing dPLY-formol, PhtA, PhtB, PhtD, PhtE PhtX and Pht protein fusions, such as PhtDE fusions and PhtBE fusions. Compounds (see International Publication Nos. 01 / 98334 and 03 / 54007) can also be used. It can be used with other proteins, such as ovalbumin and keyhole limpet. Purified syrup of mosyanin (KLH), bovine serum albumin (BSA), or tuberculin. Protein derivatives (PPD), PorB (derived from Neisseria meningitidis) , PD (Haemophilus influenzae protein D; for example, see European Patent No. 0594610) (See reference), or their immunologically functional equivalents, synthetic peptides (European Patent No. 03788) (See Specification No. 81 and European Patent No. 0427347), heat shock proteins (See International Publication Nos. 93 / 17712 and 94 / 03208), Pertussis Protein (International Publication No. 98 / 58668 and European Patent No. 0471177) (Reference), cytokines, lymphokines, growth factors or hormones (International Publication No. 91 / 01) See issue 146), N19 protein (Baraldoi et al., 2004, I From various pathogen-derived antigens such as (see Infect Immun 72:4884-7) Artificial protein containing multiple human CD4+ T cell epitopes (Falugi et al. (See l., 2001, Eur J Immunol 31:3816-3824), iron Intake proteins (see International Publication No. 01 / 72337), C. difficile (C. Toxin A or B of difficile (see International Publication No. 00 / 61761), Biniflagelin (Ben-Yedidia et al., 1998, Immunol) (See Lett 64:9) can also be used as a carrier protein.

[0429] When a polyvalent vaccine is used, the second carrier is one of the antigens in the polyvalent vaccine. The above can be used. The second carrier protein is preferably non-toxic and non-reactive. It is a protein that can be obtained in sufficient quantity and purity. The second carrier protein The substance also conjugates or binds to antigens, such as Streptococcus pneumoniae polysaccharides, and provides immunity to the antigen. Enhance virulence. Carrier proteins should follow standard conjugation procedures. Each capsular polysaccharide that is not conjugated to the first carrier protein is conjugated to the same second carrier protein. It can be conjugated to proteins (for example, each capsular polysaccharide molecule can be conjugated to a single carrier protein). (conjugated to the first carrier protein). Membrane polysaccharides can be conjugated to two or more carrier proteins (each capsule polysaccharide molecule is single (Conjugated to one carrier protein). In such embodiments, the same serum Each type of capsular polysaccharide is typically conjugated to the same carrier protein. CRM1 76, CRM228, CRM45 (Uchida et al., 1973, J Bio l Chem 218:3838-3844);CRM9, CRM45 CRM102, CRM103 and CRM107, as well as by Nicholls and Youle Genetically Engineered Toxins, Ed:Frankel Other mutations described in Maecel Dekker Inc, 1992; Gl Deletion or mutation of u-148 to Asp, Gln, or Ser, and / or A The mutation of la158 to Gly, and U.S. Patent No. 4,709,017 or Other variants disclosed in U.S. Patent No. 4,950,740; at least one Mutations in the residues Lys516, Lys526, Phe530, and / or Lys534 , and U.S. Patent No. 5,917,017 or U.S. Patent No. 6,455,67 Other variations disclosed in item 3; or disclosed in U.S. Patent No. 5,843,711 Other DT variants, such as fragments that have been identified, can be used as a second carrier protein. ru.

[0430] Conjugation by reductive amination The covalent bonding of polysaccharides to carrier proteins is achieved by the amine-reactive portion on the polysaccharide being the protein. This is carried out by reductive amination, which involves direct bonding to the primary amine group (mainly lysine residues). It is possible. As is well known, the reductive amination reaction proceeds via a two-step mechanism. First, the Schiff base intermediate of formula R-CH=N-R' is the aldehyde group (R-CH) on molecule 1. It is formed by the reaction of O) with the primary amine group (R'-NH2) on molecule 2. In this process, the Schiff base is reduced to form an amino compound of the formula R-CH2-NH-R'. Many reducing agents can be used, but in most cases sodium cyanoborhydride is used. Highly selective reducing agents such as um (NaCNBH3) are used in Schiff bases. It is used to specifically reduce only the imine functional group.

[0431] Since all polysaccharides have an aldehyde functional group (terminal aldehyde functional group) at the end of the chain, Conjugation methods involving the reductive amination of polysaccharides are very commonly applied. If there are no other aldehyde functional groups (intrachain aldehyde functional groups) in the repeating unit, Such methods can yield a conjugate in which a polysaccharide molecule is bound to a single molecule of a carrier protein. This makes it possible.

[0432] Typical reducing agents are cyanoborohydride salts, such as sodium cyanoborohydride. A commonly used imine-selective reducing agent is sodium borocyanohydride, Other cyanoboron cyanohydride salts, including potassium cyanoboron cyanohydride, can be used. Starting cyanide levels and conjugate levels in sodium borohydride reagent lots Differences in residual cyanide during the reaction lead to inconsistent conjugation performance. Conjugate size and conjugate Ps vs CRM 197 Variable product attributes such as ratios This may result in: controlling the level of free cyanide in the final reaction product and / or By reducing this, the variability of the conjugation can be reduced.

[0433] Unreacted residual aldehydes on polysaccharides can be removed by adding a strong reducing agent such as sodium borohydride. It may be reduced by [a certain agent]. Generally, the use of a strong reducing agent is preferred. However, For some polysaccharides, it is preferable to avoid this step. For example, Streptococcus pneumoniae Serotype 5 contains ketone groups that readily react with strong reducing agents. In this case, the reduction step is It is preferable to bypass the polysaccharide antigen structure to protect it.

[0434] After conjugation, the polysaccharide protein conjugate is purified and concentrated / diaphytic. Retraction, ultrafiltration, precipitation / elution, column chromatography, and deep filtration Excess conjugation Removes reagents, residual free proteins, and free polysaccharides. For example, U.S. 6 See Specification No. 146,902. In one embodiment, the purification step is by ultrafiltration. It is.

[0435] Pneumococcal conjugate composition The present invention relates to polysaccharide serotype-conjugates described herein and / or known in the art. The gate combination comprises a pharmaceutically acceptable carrier and the above-mentioned SNE. , pneumococcal conjugate composition consisting essentially of them, or alternatively consisting of them The product is provided. The composition is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 2 7, 28, 29, 30, 31, 32, 33, 34, or 35 or more different polysaccharide carriers It may contain protein conjugates, may essentially consist of them, or may not consist of them. Each conjugate may be a different capsule conjugated to a carrier protein. (The carrier protein contains sugars, one specific carrier protein or two or more different (It may be a carrier protein). In one embodiment, the capsular polysaccharide is serotype 1 of Streptococcus pneumoniae. 2, 3, 4, 5, 6A, 6B, 6C, 7C, 7F, 8, 9N, 9V, 10A, 11A, 1 2F, 14, 15A, 15B, 15C, 16F, 17F, 18C, 19A, 19F, 20 (20A or 20B), 22F, 23A, 23B, 23F, 24F, 33F, 35B Selected from at least one or more of 35F or 38. In this embodiment, the serotype is conjugated to the carrier protein CRM197.

[0436] In some embodiments, the polysaccharides contained in the polysaccharide carrier protein conjugate are blood Clear type: 1, 2, 3, 4, 5, 6A, 6B, 6C, 7C, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15A, 15B, 15C, 16F, 17F, 18C, 19A, 1 9F, 20 (20A and / or 20B), 22F, 23A, 23B, 23F, 24 Selected from polysaccharides chosen from the group of serotypes consisting of F, 33F, 35B, 35F, or 38. Selected. In other embodiments, the serotype group is 4, 6B, 9V, 14, 18C, 19F, and 23F. In other embodiments, the serotype group is 1, 3, 4, 5, 6A, 6B It consists of 7F, 9V, 14, 18C, 19A, 19F, and 23F. In other embodiments, The serotype groups are 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, It consists of 19F, 22F, 23F, and 33F. In other embodiments, the group of serotypes is 1 , 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, It consists of 18C, 19A, 19F, 22F, 23F, and 33F. In other embodiments, The serotype groups are 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, and 12F. , 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, It consists of 33F and 35B. In other embodiments, the serotype group is 1, 3, 4, 5, 6 A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-oacetylation -15B, 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and It consists of 35B. In other embodiments, the serotype group is 1, 3, 4, 5, 6A, 6B, 7F , 8, 9V, 10A, 11A, 12F, 14, 15A, 15C, 18C, 19A, 19F , consists of 22F, 23B, 23F, 24F, 33F, and 35B. In other embodiments, it consists of 22F, 23B, 23F, 24F, 33F, and 35B. The serotype groups are 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12 F, 14, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B , consists of 23F, 24F, 33F, and 35B. In other embodiments, the group of serotypes is 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A De-O-acetylation - 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23 The group consists of B, 23F, 24F, 33F, and 35B. In other embodiments, the group of serotypes is , 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15 A, 15C, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24 It consists of F, 33F, and 35B.

[0437] In some embodiments, the carrier protein contained in the polysaccharide carrier protein conjugate The substances are OMPC, PhtD, pLys, DT (diphtheria toxoid), and TT (tetanus). Toxoids), TT fragment C, pertussis toxoid, cholera toxoid, and CRM19 Selected from 7. In other embodiments, the carrier protein is CRM197.

[0438] Dosage The compositions and formulations of the present invention help to maintain the health of people who are susceptible to infectious diseases, such as pneumococcal infections. To protect or treat, the composition, formulation, or vaccine is administered systemically to a patient who needs it. Alternatively, it can be used by administration via a mucosal route. In one embodiment, The present invention relates to pneumonia, comprising administering an immunologically effective amount of the immunogenic composition of the present invention to a human. This invention provides a method for inducing an immune response against streptococcal capsular polysaccharide conjugates. In terms of form, the present invention relates to the immunogenicity of the immunogenic composition, formulation, or vaccine of the present invention. The present invention provides a method for vaccinating humans against pneumococcal infection, including the step of administering a vaccine to humans. do.

[0439] The optimal amount of an ingredient for a particular composition, formulation, or vaccine is appropriate for the target immune system. This can be confirmed by standard studies involving observation of the epidemic response. For example, in another embodiment... Therefore, the dosage for human vaccination is determined by extrapolating from animal studies to human data. The dosage is determined. In another embodiment, the dosage is determined empirically.

[0440] The method of the present invention is for invasive infections (meningitis, pneumonia, and bacteremia) and non-invasive infections ( Primary clinical conditions caused by Streptococcus pneumoniae, including both acute otitis media and sinusitis. It can be used to prevent and / or reduce the syndrome.

[0441] The composition, formulation, or vaccine of the present invention may be administered intramuscularly, intraperitoneally, intradermally, or subcutaneously. By injection via the route, or by mucosal administration to the oral / gastrointestinal tract, respiratory tract, or urogenital tract. It may include one or more of the following. In one embodiment, intranasal administration is used to treat pneumonia or otitis media. It is used for treatment (it can more effectively prevent nasopharyngeal carriage of Streptococcus pneumoniae). (This allows the infection to be weakened in its early stages.)

[0442] The amount of conjugate in each vaccine (or composition or formulation) dose is significant and harmful. It can be selected as a dose that induces an immune defense response without action. Such a dose is used in pneumococcal blood This may vary depending on the clear form. Generally, in the case of polysaccharide conjugates, each dose is 0.1 to 1 It contains 00 μg of each polysaccharide, particularly 0.1-10 μg, and more specifically 1-5 μg. For example, Each dose is 100, 150, 200, 250, 300, 400, 500, or 750 mg. g, or 1, 1.5, 2, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 25, 30, 40, 50, 60, 70, 8 It may contain 0, 90, or 100 μg.

[0443] According to any of the methods of the present invention, in one embodiment, the subject is a human. In terms of administration methods, human patients include infants (under 1 year old), toddlers (approximately 12 to 24 months old), and In other embodiments, the human patient is an elderly patient (>65 years old). The composition of the present invention is also suitable for older children, adolescents, and adults (e.g., 18 to 45 years of age). It is also suitable for use by those aged 18 to 65.

[0444] In one embodiment of the method of the present invention, the composition, formulation, or vaccine of the present invention is administered as a single dose. It is administered as follows. In another embodiment, the composition, formulation, or vaccine is administered two, three times. Or administered four or more times with sufficient intervals between doses. For example, a composition, formulation, or vaccine The medication is administered at intervals of 1, 2, 3, 4, 5, or 6 months, or any combination thereof. It is possible. The immunization schedule can follow that specified for the pneumococcal vaccine. For example, the daily life of infants and toddlers with invasive diseases caused by Streptococcus pneumoniae. The usual schedule is at 2, 4, 6, and 12-15 months of age. Therefore, In one embodiment, the composition, formulation, or vaccine is used for 2, 4, 6, and 12-15 month olds. It is administered as a four-dose series.

[0445] The composition, formulation, or vaccine of the present invention also contains one or more proteins derived from Streptococcus pneumoniae. It may contain septic material. Examples of Streptococcus pneumoniae proteins suitable for inclusion include those published in international patent applications. This includes those identified in issues 02 / 083855 and 02 / 053761. .

[0446] formulation In the following embodiments of the formulation, the composition is a pharmaceutical composition and / or an immunogenic composition. This refers to a and / or single-dose vaccine composition. In some embodiments, the following is described herein. One or more compounds and one or more Streptococcus pneumoniae polysaccharides or one or more Streptococcus pneumoniae polysaccharides A composition comprising a body protein conjugate is provided. In some embodiments, The compounds described herein, and at least 7, or at least 10, or at least 1 3, or at least 15, or at least 20, or at least 24, or fewer The Streptococcus pneumoniae polymorphism contains at least 27, or at least 30 or more, serotypes of Streptococcus pneumoniae. A composition is provided that includes a sugar or a Streptococcus pneumoniae polysaccharide carrier protein conjugate. In some embodiments, the compounds described herein are used with 20, 21, 22, 23, 24 , 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, Pneumococcus polysaccharide or lung containing 38, 39, or 40 or more serotypes of Streptococcus pneumoniae. A composition is provided that includes a Streptococcus flammosa polysaccharide carrier protein conjugate. In this embodiment, the compounds described herein are used, along with serotypes 4, 6B, 9V, 14, 18C, and 1 A Streptococcus pneumoniae polysaccharide carrier protein containing serotypes 9F and 23F. A composition comprising a crystalline conjugate is provided. In some embodiments, this specification The compounds listed, and serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 1 Streptococcus pneumoniae polysaccharides containing serotypes 9A, 19F, and 23F. A composition comprising a body protein conjugate is provided. In some embodiments, The compounds described herein, and serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 1 Includes Streptococcus pneumoniae serotypes consisting of 8C, 19A, 19F, 22F, 23F, and 33F. A composition is provided that contains a Streptococcus pneumoniae polysaccharide carrier protein conjugate. In some embodiments, the compounds described herein are used in combination with serotypes 1, 3, 4, 5, and 6A. , 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 1 Streptococcus pneumoniae containing serotypes 9F, 22F, 23F, and 33F A composition comprising a microbial polysaccharide carrier protein conjugate is provided. Several embodiments In this state, the compounds described herein and serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9 V, 10A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23B Pneumonia Streptococcus serotypes including 23F, 24F, 33F, and 35B A composition is provided that includes a chainococcal polysaccharide carrier protein conjugate. In terms of application, the compounds described herein, along with serotypes 1, 3, 4, 5, 6A, 6B, 7F, and 9, are used. V, 10A, 12F, 14, 15A, de-O-acetyl 15B, 18C, 19A, 19F, The serotypes of Streptococcus pneumoniae consist of 22F, 23B, 23F, 24F, 33F, and 35B. A composition is provided that contains a Streptococcus pneumoniae polysaccharide carrier protein conjugate. In some embodiments, the compounds described herein are used with serotypes 1, 3, 4, 5, and 6A. 6B, 7F, 9V, 10A, 12F, 14, 15A, 15C, 18C, 19A, 19F, The serotypes of Streptococcus pneumoniae consist of 22F, 23B, 23F, 24F, 33F, and 35B. A composition is provided that contains a Streptococcus pneumoniae polysaccharide carrier protein conjugate. In some embodiments, the compounds described herein are used with serotypes 1, 3, 4, 5, and 6A. 6B, 7F, 9V, 10A, 12F, 14, 15A, 15B, 18C, 19A, 19F, The serotypes of Streptococcus pneumoniae consist of 22F, 23B, 23F, 24F, 33F, and 35B. A composition is provided that contains a Streptococcus pneumoniae polysaccharide carrier protein conjugate. In some embodiments, the compounds described herein are used with serotypes 1, 3, 4, 5, and 6A. 6B, 7F, 9V, 10A, 12F, 14, 15A, De-O-acetyl 15B, 18C, 1 Pneumonia association consisting of 9A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B A composition containing a Streptococcus pneumoniae polysaccharide carrier protein conjugate containing a serotype of Streptococcus. A substance is provided. In some embodiments, the compound described herein and serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 10A, 12F, 14, 15A, 15C, 18C, 1 Pneumonia association consisting of 9A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B A composition containing a Streptococcus pneumoniae polysaccharide carrier protein conjugate containing a serotype of Streptococcus. A substance is provided. In some embodiments, the compound described herein and serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15B , 18C, 19A, 19F, 22F, 23B, 23F, 24F, 33F, and 35B A conjugate containing various serotypes of Streptococcus pneumoniae and Streptococcus pneumoniae polysaccharide carrier protein A composition comprising the compounds described herein and blood is provided. In some embodiments, the compounds described herein and blood are provided. Clear type 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 1 5A, de-O-acetyl 15B, 18C, 19A, 19F, 22F, 23B, 23F, 24 A Streptococcus pneumoniae polysaccharide carrier containing Streptococcus pneumoniae serotypes consisting of F, 33F, and 35B. A composition comprising a protein conjugate is provided. In some embodiments, this The compounds described in the specification, and serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A , 11A, 12F, 14, 15A, 15C, 18C, 19A, 19F, 22F, 23B, Pneumonia chains containing Streptococcus pneumoniae serotypes consisting of 23F, 24F, 33F, and 35B A composition comprising a cocci polysaccharide carrier protein conjugate is provided. Several implementations In terms of form, the compounds described herein and serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15B, 16F, 18C, 19A, 19 Pneumonia chain consisting of F, 22F, 23A, 23B, 23F, 24F, 33F, and 35B A composition comprising a Streptococcus pneumoniae polysaccharide carrier protein conjugate containing a cocci serotype. In some embodiments, the compounds described herein are used in combination with serotypes 1, 3, and 4. , 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, Cetyl 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 2 Streptococcus pneumoniae polysaccharides containing serotypes 4F, 33F, and 35B A composition comprising a body protein conjugate is provided. In some embodiments, The compounds described herein, and serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10 A, 11A, 12F, 14, 15A, 15C, 16F, 18C, 19A, 19F, 22F Streptococcus pneumoniae serotypes consisting of 23A, 23B, 23F, 24F, 33F, and 35B A composition is provided that includes a Streptococcus pneumoniae polysaccharide carrier protein conjugate containing a Streptococcus pneumoniae polysaccharide carrier protein conjugate. ru.

[0447] In some embodiments, the above composition is used with other Streptococcus pneumoniae serums known in the Art. Additional 1, 2, 3, 4, or 5 types of Streptococcus pneumoniae polysaccharide carrier protein con Contains jugate.

[0448] In some embodiments, the above compositions are from groups 7C, 35F, 21, 34, 16F, and 9. Contains other Streptococcus pneumoniae serotypes selected from N, 31, 17F, 23A, and 27. an additional 1, 2, 3, 4, or 5 Streptococcus pneumoniae polysaccharide carrier protein conjugate It contains.

[0449] In some embodiments, the above compositions are selected from groups 7C, 35F, 21, and 34. One or two additional Streptococcus pneumoniae polysaccharide carriers containing other selected Streptococcus pneumoniae serotypes Contains protein conjugates.

[0450] In some embodiments, the above compositions are derived from groups 16F, 9N, 31, and 17F. An additional 1 or 2 Streptococcus pneumoniae polysaccharides containing other selected serotypes of Streptococcus pneumoniae. Contains body protein conjugates.

[0451] In some embodiments, the above composition is used for other lungs selected from groups 23A and 27. An additional 1 or 2 Streptococcus pneumoniae polysaccharide carrier protein constitutive containing a Streptococcus serotype Contains jugate.

[0452] In some embodiments, the above composition is such that the protein is the carrier protein CRM197 It contains a polysaccharide carrier protein conjugate.

[0453] In some embodiments, about 1 μg to about 200 mg of the compound of the present invention, or its pharmaceutical ingredients. A moderately acceptable salt and at least one Streptococcus pneumoniae polysaccharide carrier protein conjugate A composition is provided that includes and, each of the conjugates per 0.5 mL of vaccine formulation It is present in concentrations ranging from approximately 0.01 μg to approximately 100 μg.

[0454] In some embodiments, about 0.02 μg to about 40 mg of the compound of the present invention, or the A pharmaceutically acceptable salt and at least one Streptococcus pneumoniae polysaccharide carrier protein conjugate A composition is provided comprising a conjugate and a vaccine formulation, where each conjugate is present in 0.1 mL of the vaccine formulation. It exists at concentrations ranging from approximately 0.002 μg to approximately 20 μg.

[0455] In some embodiments, about 50 μg to about 2.1 mg of the compound of the present invention, or the drug thereof, is used. A scientifically acceptable salt and at least one Streptococcus pneumoniae polysaccharide carrier protein conjugate A composition is provided containing and, each of the conjugates per 0.5 mL of the vaccine formulation It is present in concentrations ranging from approximately 0.002 μg to approximately 20 μg.

[0456] In some embodiments, about 50 μg to about 10 mg of the compound of the present invention, or its pharmaceuticals A moderately acceptable salt and at least one Streptococcus pneumoniae polysaccharide carrier protein conjugate A composition is provided that includes and, each of the conjugates per 0.5 mL of vaccine formulation It exists at concentrations ranging from approximately 0.002 μg to approximately 20 μg.

[0457] In some embodiments, about 50 μg to about 10 mg of the compound of the present invention, or its pharmaceuticals A moderately acceptable salt and at least one Streptococcus pneumoniae polysaccharide carrier protein conjugate A composition is provided that includes and, each of the conjugates per 0.5 mL of vaccine formulation It exists at concentrations ranging from approximately 0.002 μg to approximately 20 μg.

[0458] In some embodiments, about 1 μg to about 200 mg of the compound of the present invention, or its pharmaceutical ingredients. A moderately acceptable salt and at least one Streptococcus pneumoniae polysaccharide carrier protein conjugate A composition comprising the above is provided, and each of the conjugates is prepared as a co-freeze-dried formulation. It is present in concentrations of approximately 0.01 μg to 100 μg per 0.5 mL of the vaccine preparation.

[0459] In some embodiments, about 1 μg to about 200 mg of the compound of the present invention, or its pharmaceutical ingredients. A moderately acceptable salt, 1 μg to about 1 mg of aluminum in the form of APA, and at least 1 A composition is provided comprising a Streptococcus pneumoniae polysaccharide carrier protein conjugate, Each jugate contains approximately 0.5 mL of the vaccine preparation prepared as a co-freely dried formulation. It exists at concentrations ranging from 0.01 μg to approximately 100 μg.

[0460] In some embodiments, as highlighted in the various embodiments described above, about 0.05 μg The present invention comprises approximately 200 mg of the compound of the present invention, or a pharmaceutically acceptable salt thereof, and SPAN- A composition is provided that further comprises 85, PS-80, or PS-20, and squalene. In some embodiments, as highlighted in the various embodiments described above, about 0.05 μm g to approximately 200 mg of the compound of the present invention, or a pharmaceutically acceptable salt thereof, SPAN A composition further comprising -85, PS-20, and squalene is provided. Another embodiment In this embodiment, the compound is compound A-1, A-2, or A-3. The compounds are compounds B-1, B-2, B-3, B-4, or B-5. , or B-6, or B-7, or B-8, or B-9, or B-10, or B-11, or B-12, or B-13, or B-14, or B-15, or This is B-16, or B-17, or B-18. In another embodiment, the compound is a compound Item C-1, or C-2, or C-3, or C-4, or C-5. Another implementation Morphologically, the compound is compound D-1, or D-2, or D-3, or D-4, It is D-5 or D-6.

[0461] The compositions of the present invention can be administered subcutaneously, topically, orally, on the mucous membrane, intravenously, or intramuscularly. The composition is administered in an amount sufficient to induce a defensive response. The composition is administered via various routes, e.g. For example, it can be administered orally, parenterally, subcutaneously, intramucosally, or intramuscularly. The dosage will vary depending on the patient's overall health, sex, weight, and age, as well as the route of administration. It is possible.

[0462] The compositions of the present invention, as highlighted in the various embodiments described above, are called immunogenic compositions. It can happen.

[0463] The compositions of the present invention, as highlighted in the various embodiments described above, are vaccines or vaccines. It is sometimes called a composition.

[0464] In each of the above embodiments, the composition contains a Streptococcus pneumoniae polysaccharide carrier protein conjugate. It also includes.

[0465] The present invention provides a method for treating or preventing pneumococcal disease by administering the above composition. To provide.

[0466] The present invention provides the use of the above-mentioned compositions for treating or preventing pneumococcal diseases. .

[0467] All publications referenced herein refer to methodologies and that may be used in connection with the present invention. Incorporated by reference for the purpose of describing and disclosing materials. Nothing in this specification This is interpreted as an acknowledgment that the present invention does not have any prior rights to such disclosure by prior inventions. It should not be done.

[0468] Preferred embodiments of the present invention have been described with reference to the attached drawings, but the present invention is not limited to those The scope or intent of the invention is not limited to the exact embodiments, as defined in the appended claims. It is understood that various changes and modifications may be used by those skilled in the art without departing from the intent. I want to be understood.

[0469] The following examples illustrate the present invention, but are not intended to limit it.

[0470] [Example 1] To prepare compounds of formulas I, Ia, II, IIa, III, IIIa, IV, and IVa. Common methods for doing so The compound is prepared according to methods known to those skilled in the art of organic synthesis, or is readily available. It can be prepared from excipients. Representative methods useful for preparing the compound are described in the following examples. The following alternative synthetic routes and similar structures will be apparent to those skilled in the art of organic synthesis.

[0471] Those skilled in the art of organic synthesis will recognize the polycyclic and / or heterocyclic cores contained in the compounds of the present invention. The synthesis of a derivative aimed at specific functional groups (i.e., chemical compatibility with specific reaction conditions) It will be recognized that protection of the chemical group may be necessary for the various functional groups of these compounds. Suitable protecting groups and methods for their installation and removal are well known in the field of organic chemistry. Many of these methods are outlined in Greene et al., Protective Groups in Organic Synthesis,Wiley-Inter This can be found in *Science*, New York, (1999).

[0472] Those skilled in organic synthesis will also know one method for the synthesis of the polycyclic heterocyclic core of the compound of the present invention. You will recognize that the path may be more desirable depending on the selection of the appendage substituents.

[0473] Furthermore, those skilled in the art can, in some cases, avoid the incompatibility of functional groups and, accordingly, modify the synthesis process. In order to adjust the course, recognize that the order of reactions may differ from the order presented herein. It will probably happen.

[0474] Polycyclic intermediates useful for fabricating polycyclic and / or heterocyclic cores of the present invention The preparation of the body is documented and published by Elsevier and ARKatritz. Comprehensive He Official doctrines such as "Terocyclic Chemistry" editions I, II, and III It is described. The operation of the required substitution patterns is published by Elsevier, D Comprehe nsive Organic Chemistry”;ARKatritzky&R Edited by JK Taylor: "Comprehensive Organic c Functional Group Transformations, and "Co" published by Wiley-CVH and edited by RCLarock Official terms such as "Professional Organic Transformation" It is also mentioned in the available chemical literature summarized in the book.

[0475] The starting materials used and the intermediates prepared using the methods described in the following examples This includes, but is not limited to, filtration, distillation, crystallization, chromatography, etc., if desired. Such materials can be isolated and purified using conventional techniques that do not specify physical constants. It can also be characterized using conventional means, including spectral data.

[0476] Those skilled in the art can refer to the published literature and Zheng's "Formulation and Analysis" tical Development for Low-Dose Oral Drug Products, as listed in textbooks such as Wiley, 2009, ISBN They are likely familiar with standard formulation techniques.

[0477] Preparation of compounds and intermediates The present invention will be explained by the following examples. For all examples, the standard known to those skilled in the art will be described. Standard post-processing and purification methods can be used. Unless otherwise specified, all temperature Degrees are expressed in degrees Celsius (℃). Unless otherwise specified, all reactions are carried out at room temperature. The synthetic methodologies described in the document illustrate applicable chemistry through the use of specific examples. This is an intention and does not indicate the scope of this disclosure.

[0478] General method Commercially available solvents, reagents, and intermediates were used as received. Non-commercially available intermediates were also used. The interstitial material was prepared by the method described below. 1 The H NMR spectrum is from Me4Si. Reported as ppm downfield, the number of protons, multiplicity, and binding constants are, The values ​​are shown in Hertz within the arc. If LC / MS data is shown, the observed parent ion is As shown, flash column chromatography uses pre-packed normal-phase silica or This was performed using bulk silica.

[0479] [Example 2] Method for producing intermediates of the compound of the present invention Intermediate 1-1 Preparation of compound Int.1-1 [ka] Methyl(7-(butylamino)-1H-pyrazolo[4,3-d]pyrimidine-5-yl) ) Carbamate [ka]

[0480] Step 1: Methyl(7-hydroxy-1H-pyrazolo[4,3-d]pyrimidine-5-i Carbamate Methyl 4-amino-1H-pyrazole-5-carboxylate (2g, 14.17mm) ol) and 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopsoideu A mixture of 2.92g of 14.17 mmol of phosphate (A) stirred in 20mL of MeOH is mixed with AcO H (4.87 mL, 85 mmol) was added at ambient temperature. The resulting mixture was stirred for 16 hours. Mix the mixture, then add NaOMe (25.5 g, 142 mmol) in MeOH dropwise. After the addition was complete, the reaction mixture was acidified to pH 1-2 with AcOH. The resulting solid was filtered. Collected by, then washed with CH3CN (200 mL), and then dried in vacuum. The title compound was obtained. MS m / z(M+H) + Calculated value: 210.1, Measured value: 210.1 . 1 H-NMR(400 MHz,DMSO-d6)δ 7.83(s,1H),3.6 7(s,3H).

[0481] Step 2: Methyl(7-(butylamino)-1H-pyrazolo[4,3-d]pyrimidine- 5-yl)carbamate Methyl(7-hydroxy-1H-pyrazolo[4,3-d]pyrimidine-5-yl)cal Bamate (5g, 23.90 mmol), Butan-1-amine (4.73 ml, 47.8 DMSO (100 mL) of DBU (3.92 mL, 26.3 mmol) BOP (12.69 g, 28.7 mmol) was added to the stirred mixture at ambient temperature. The resulting mixture was heated to 60°C for 3 hours. The resulting mixture was cooled to ambient temperature, and then , filter, then reverse-phase chromatography (0-50% formic acid modifier containing 0.1% formic acid modifier) The title compound was obtained by direct purification using CH3CN / water. MS m / z(M+H) + Calculated value: 265.1, measured value: 265.1. 1 H-NMR (400 MHz, DMSO-d 6)δ 12.94(br.,1H),9.89(s,1H),8.14-7.99(m ,2H),3.67(s,3H),3.56-3.51(m,2H),1.66-1.5 8(m,2H),1.42-1.33(m,2H),0.92(t,J=7.2 Hz, 3H).

[0482] Intermediate 2-1 Preparation of compound Int.2-1 [ka] 5-Azido-N-butyl-1H-pyrazolo[4,3-d]pyrimidine-7-amine [ka]

[0483] Step 1: N-butyl-5-chloro-1H-pyrazolo[4,3-d]pyrimidine-7-a Min 5,7-Dichloro-1H-pyrazolo[4,3-d]pyrimidine (3g, 15.87mm) Mixture of ol) in THF (30 mL), DIEA (3.08 g, 23.81 mm) at 0°C. (ol) and butan-1-amine (1.741 g, 23.81 mmol) were added. After the addition was complete, the mixture was heated to ambient temperature and stirred for 2 hours. The resulting mixture was then mixed with water (2 Diluted with 00 mL, then extracted with ethyl acetate (3 × 300 mL). Combined organic The extract was washed with brine (2 x 300 mL), then dried with (Na2SO4), and then... Then, it was filtered. The filtrate was concentrated to obtain the title compound, which was used directly in the next step without purification. Used. MS m / z(M+H) + Calculated value: 226.1, measured value: 226.2.

[0484] Step 2: 5-azido-N-butyl-1H-pyrazolo[4,3-d]pyrimidine-7-a Min Ambient temperature N-butyl-5-chloro-1H-pyrazolo[4,3-d]pyrimidine-7- Amine (3.5g, 15.51 mmol) in AcOH (6mL) and EtOH (24mL) To the mixture in (L), add sodium azide (1.512 g, 23.26 mmol), and then... Next, the mixture was heated to 100°C for 3 hours. The resulting mixture was cooled to ambient temperature, and then... Then, it was diluted with water (200 mL) and extracted with ethyl acetate (3 × 300 mL). The combined organic extracts were washed with brine (2 x 300 mL), and then dried (Na2S O4) was then filtered, and the filtrate was concentrated. The crude product was subjected to silica gel chromatography. The compound was subjected to a filtration solution (0-20% toluene / petroleum ether) to obtain the title compound. m / z(M+H) + Calculated value: 233.1, measured value: 233.1.

[0485] Using the procedure described for intermediate 2-1, prepare the appropriate reagent for butan-1-amine. The following compounds were prepared by substitution.

[0486] [Table 2]

[0487] Intermediate 2-3 Preparation of compounds Int.2-3 [ka] 5-Azido-N-butyl-3-methyl-1H-pyrazolo[4,3-d]pyrimidine-7 -amine [ka]

[0488] Step 1: 5-Azido-N-butyl-3-iod-1H-pyrazolo[4,3-d]pyrim Zin-7-amine 5-Azido-N-butyl-2H-pyrazolo[4,3-d]pyrimidine-7-amine(1 In a solution of 4.31 mmol (g) in DMF (30 mL), add N-iodosuccinimide (1 (0.937g, 8.61 mmol) was added, and the mixture was then heated to 40°C. The mixture was left overnight. After heating, the mixture is cooled to room temperature, and then diluted with 10% Na2SO3 (40 mL). The obtained solid was collected by filtration, then washed with water (10 mL x 3 times), and then... The compound was then dried under vacuum to obtain the title compound. MS m / z(M+H) + Calculated value: 35 9.0, actual measured value 359.0.

[0489] Step 2: 5-Azido-N-butyl-3-methyl-1H-pyrazolo[4,3-d]pyrim Zin-7-amine 5-Azido-N-butyl-3-iod-2H-pyrazolo[4,3-d]pyrimidine-7 -amine (1g, 2.79 mmol) with 1,4-dioxane (10mL) and H2O( In a 1 mL solution, add Pd(dppf)Cl2 (0.204 g, 0.279 mmol), K 3PO4 (1.185g, 5.58mmol), and 2,4,6-trimethyl-1,3 ,5,2,4,6-trioxatrivolinan (3.51g, 13.96mmol) in N2 The mixture was then added below, and the mixture was heated to 100°C overnight. The resulting mixture was cooled to room temperature. Next, dilute with HCl (30 mL), then dry with (Na2SO4), then The mixture was then filtered, and the filtrate was concentrated. The crude product was subjected to silica gel chromatography (30 The title compound was obtained by subjecting it to ~70% ammonium ether (petroleum ether). MS m / z(M +H) + Calculated value: 247.1, measured value: 247.4.

[0490] Intermediate 3-1 Preparation of compound Int.3-1 [ka] tert-butyl4-(4-(hydroxymethyl)-3,5-dimethoxyphenyl) Perazine-1-carboxylate [ka]

[0491] Step 1: tert-butyl 4-(4-formyl-3,5-dimethoxyphenyl)piper Zin-1-carboxylate 4-bromo-2,6-dimethoxybenzaldehyde (5g, 20.40 mmol) In a 20 mL mixture of Luen, tert-butylpiperazine was added under an argon atmosphere. 1-Carboxylate (5.70g, 30.6mmol), RuPhos (1.904g) , 4.08 mmol), Pd2(dba)3 (1.868 g, 2.040 mmol), Add NaOtBu (5.88g, 61.2mmol), then mix the contents to 100 The mixture was heated to °C. After 6 hours, it was cooled to ambient temperature and then diluted with water (50 mL). Next, it was extracted with ethyl acetate (3 x 80 mL). The combined organic extracts were then prepared as brine (3 Wash with 50 mL of water, then dry with (Na2SO4), then filter, then... The filtrate was concentrated. The crude product was subjected to silica gel chromatography (0-100% alkyl silica gel). The title compound was obtained by subjecting it to (DCM). MS m / z(M+H) + Calculated value: 351.2 The measured value was 351.3.

[0492] Step 2: tert-butyl 4-(4-(hydroxymethyl)-3,5-dimethoxymethyl (Nyl)piperazine-1-carboxylate tert-butyl4-(4-formyl-3,5-dimethoxyphenyl)piperazine-1 -Carboxylate (3g, 8.56 mmol) stirred in EtOH (10mL) NaBH4 (0.389 g, 10.27 mmol) was added at ambient temperature. After 15 minutes, The mixture was diluted with water (15 mL) and then extracted with Et2O (3 × 50 mL). The prepared organic extract was washed with brine (3 x 50 mL), and then dried (Na2SO4 ), then filtered. Next, the filtrate was concentrated to obtain the title compound, which was then processed without purification. It was used directly in the process. MS m / z(M+H) + Calculated value: 353.2, Measured value: 353. 3.

[0493] Intermediate 4-1 Preparation of compound Int.4-1 [ka] tert-butyl(4-(chloromethyl)-3,5-dimethoxybenzyl)(methyl) Carbamate [ka]

[0494] Step 1: tert-butyl(4-formyl-3,5-dimethoxybenzyl)(methyl) Carbamate 4-Bromo-2,6-dimethoxybenzaldehyde (6g, 24.48 mmol), N -(tert-butoxycarbonyl)-N-methylglycine (9.26g, 49.0mg) ol), Ir[dF(CF3)ppy]2(dtbbpy)PF6(0.275g, 0. 245 mmol), and [Ni(dtbbpy)(H2O)4]Cl2 (0.575 g Combined (1.224 mmol) in DMSO (120 mL). To this, BTMG (1 0 mL (49.0 mmol) was added. The mixture was sonicated until all solids were dissolved. The mixture was processed and then uniformly transferred to four screw-cap vials equipped with stirring bars. It was divided into two parts. N2 was blown into each mixture for 5 minutes. The vials were capped, and then the mixture was P ennOC Photoreactor (registered trademark) (wavelength: 420nm; LED intensity: Irradiated overnight at 100% (fan speed: 5000 rpm; stirr...

Claims

1. An immunogenic composition, (i) at least one Streptococcus pneumoniae polysaccharide carrier protein conjugate, (ii) Compounds having the structure described in formula I: 【Chemistry 1】 (In the formula, R ａ H, -OH, (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkenil, (C １ - C ６ ) alkynyl, -O(C １ -C ６ ) alkyl, -O(C １ -C ６ ) alkenyl, -O (C １ -C ６ ) Selected from alkynyl, chlorine, fluorine, and -NR'R'', the ( C １ -C ６ ) alkyl, (C １ -C ６ ) Alkenil, (C １ -C ６ ) Alkinyl, -O( C １ -C ６ ) alkyl, -O(C １ -C ６ ) alkenyl, and -O(C １ -C ６ ) Al Kinyl is -OH, -O(C) １ -C ４ ) alkyl, -O(C １ -C ４ ) Alkenyl, -O (C １ -C ４ ) 1 to independently selected from the group consisting of alkynyl, chlorine, and fluorine It may also be substituted with four substituents. R ａ’ H, -OH, (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkenil, (C １ -C ６ ) Alkinyl, -O(C １ -C ６ ) alkyl, -O(C １ -C ６ ) Alkenil, - O(C) １ -C ６ ) Selected from alkynyl, chlorine, fluorine, and -NR'R'', the above (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkenil, (C １ -C ６ ) Alkinyl, -O (C １ -C ６ ) alkyl, -O(C １ -C ６ ) alkenyl, and -O(C １ -C ６ )a Lukinyl is -OH, -O(C) １ -C ４ ) alkyl, -O(C １ -C ４ ) Alkenil, - O(C) １ -C ４ ) One independently selected from the group consisting of alkynyl, chlorine, and fluorine It may be substituted with up to four substituents. R ａ’’ H, -OH, (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkenil, (C １ -C ６ ) Alkinyl, -O(C １ -C ６ ) alkyl, -O(C １ -C ６ ) Alkenil, -O(C) １ -C ６ ) Selected from alkynyl, chlorine, fluorine, and -NR'R'', prior Record (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkenil, (C １ -C ６ ) Alkinnil, - O(C) １ -C ６ ) alkyl, -O(C １ -C ６ ) alkenyl, and -O(C １ -C ６ ) Alkynyl is substituted with -OH, -O(C １ -C ４ )alkyl, -O(C １ -C ４ )alkenyl, -O(C) １ -C ４ ) Independently selected from the group consisting of alkynyl, chlorine, and fluorine. It may be substituted with 1 to 4 substituents. R' and R'' are H, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkenyl, and bi (C １ -C ６ ) independently selected from alkynyl, and the (C １ -C ６ ) alkyl, (C １ -C ６ ) alkenyl, and (C １ -C ６ Alkinyl is -OH, -O(C １ -C ４ ) alkyl, -O(C １ -C ４ ) Alkenyl, -O(C １ -C ４ ) Alkinyl, chlorine, It may also be substituted with 1 to 4 substituents independently selected from the group consisting of fluorine. , or R' and R'' together with the nitrogen they are bound to, bonded together do (C ３ -C ６ ) forms a heterocycloalkyl group, and the (C ３ -C ６ ) Heterocycloa Lukil is -OH, -O(C １ -C ４ ) alkyl, -O(C １ -C ４ ) Alkenyl, -O (C １ -C ４ ) 1 to independently selected from the group consisting of alkynyl, chlorine, and fluorine It may also be substituted with four substituents. R ｂ Each occurrence is H, -OH, (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkenil, (C １ -C ６ ) Alkinyl, -O(C １ -C ６ ) alkyl, -O(C １ -C ６ ) Arkeni Ru, -O(C) １ -C ６ ) Independently from alkynyl, chlorine, fluorine, or NR'R'' Selected, and the above (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkenil, (C １ -C ６ )a Lukinyl, -O(C) １ -C ６ ) alkyl, -O(C １ -C ６ ) alkenyl, and -O( C １ -C ６ Alkinyl is -OH, -O(C １ -C ４ ) alkyl, -O(C １ -C ４ ) Alkenyl, -O(C) １ -C ４ ) Independently from the group consisting of alkynyl, chlorine, and fluorine It may be substituted with 1 to 4 substituents selected by: A is (C １ -C ６ ) alkyl, heterocycloalkyl, heterocycloalkyl-C ( O)-R ｚ -, (C １ -C ４ ) Alkyl-N(R ｚ )-R ｚ -, aryl, and hetero A carbon or nitrogen bond spacer selected from aryls, the (C １ -C ６ ) Al Kill, heterocycloalkyl, aryl, and heteroaryl are -OH, (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkenil, (C １ -C ６ ) Alkinyl, -O(C １ -C ６ ) alkyl, -O(C １ -C ６ ) Alkenyl, -O(C １ -C ６ ) Alkinyl, chlorine, Substituting with 1 to 6 substituents independently selected from the group consisting of fluorine and NR'R''. It may be done as described above (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkenil, (C １ - C ６ ) Alkinyl, -O(C １ -C ６ ) alkyl, -O(C １ -C ６ ) Alkenil, oh B-O(C) １ -C ６ Alkinyl is -OH, -O(C １ -C ４ ) alkyl, -O(C １ -C ４ ) Alkenyl, -O(C １ -C ４ ) A group consisting of alkynyl, chlorine, and fluorine They may be substituted with 1 to 6 substituents that are independently selected. R ｚ Each occurrence of H or (C) is independent of H or (C) １ -C ６ ) is alkyl, B is, 【Chemistry 2】 A functional group selected from, D is (C ６ -C ２０ ) alkyl, (C ６ -C ２０ ) alkenyl, and (C ６ -C ２ ０ ) A lipid selected from alkynyl, and the above (C ６ -C ２０ ) alkyl, (C ６ -C ２０ ) alkenyl, and (C ６ -C ２０ Alkinyl is -OH, -O(C １ -C ４ ) Alkyl, -O(C) １ -C ４ ) Alkenyl, -O(C １ -C ４ ) Alkinyl, chlorine, oyo It may be substituted with 1 to 6 substituents independently selected from the group consisting of bifluorine, Or D is, 【Transformation 3】 And, Each occurrence of Z is (C ６ -C ２０ ) alkyl, (C ６ -C ２０ ) alkenyl, and (C ６ -C ２０ ) independently selected from alkynyl, and the (C ６ -C ２０ ) alkyl, (C ６ -C ２０ ) alkenyl, and (C ６ -C ２０ Alkinyl is -OH, -O(C １ -C ４ ) alkyl, -O(C １ -C ４ ) Alkenyl, -O(C １ -C ４ ) Alkinyl, chlorine, It may also be substituted with 1 to 6 substituents independently selected from the group consisting of fluorine. Ku, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, 4, or 5. An immunogenic composition comprising or a pharmaceutically acceptable salt thereof.

2. The compound has the structure described in formula Ia: 【Chemistry 4】 (In the formula, R' and R'' are H, (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkenil, oh bi (C １ -C ６ ) independently selected from alkynyl, and the (C １ -C ６ ) alkyl, (C １ -C ６ ) alkenyl, and (C １ -C ６ Alkinyl is -OH, -O(C １ -C ４ ) alkyl, -O(C １ -C ４ ) Alkenyl, -O(C １ -C ４ ) Alkinyl, chlorine, It may also be substituted with 1 to 4 substituents independently selected from the group consisting of fluorine. , or R' and R'' together with the nitrogen they are bound to, bonded together do (C ３ -C ６ ) forms a heterocycloalkyl group, and the (C ３ -C ６ ) Heterocycloa Lukil is -OH, -O(C) １ -C ４ ) alkyl, -O(C １ -C ４ ) Alkenyl, -O (C １ -C ４ ) 1 to independently selected from the group consisting of alkynyl, chlorine, and fluorine It may also be substituted with four substituents. R ｂ Each occurrence is -O(C) １ -C ４ ) is alkyl, and the -O(C １ -C ４ ) Aruki Lu is -OH, -O(C １ -C ４ ) alkyl, -O(C １ -C ４ ) Alkenyl, -O(C １ -C ４ ) one independently selected from the group consisting of alkynyl, chlorine, and fluorine k may be substituted with two substituents. A is, 【Transformation 5】 Selected from, R ｚ Each occurrence of H or (C) is independent of H or (C) １ -C ６ ) is alkyl, R ｄ Each occurrence is -OH, (C １ -C ４ ) alkyl, -O(C １ -C ４ ) alkyl, salt Selected independently from elements and fluorine, B is, 【Transformation 6】 And, D is, 【Transformation 7】 A lipid chain selected from, Any carbon on a lipid chain can be -OH, -O (C １ -C ４ ) alkyl, -O(C １ -C ４ ) Alkenyl, -O(C) １ -C ４ Even if it is substituted with alkynyl, chlorine, or fluorine often, 【Transformation 8】 It is cis or trans stereochemistry, X １ is -O-, -C(R) ２ - or -NR-, Each occurrence of R is H, (C １ -C ４ ) alkyl, (C １ -C ４ ) Alkenil, (C １ -C ４ ) Alkinyl, -OH, -O(C １ -C ４ ) alkyl, -O(C １ -C ４ ) Alkenil , -O(C １ -C ４ ) Independently selected from alkynyl, chlorine, and fluorine, m is 0, 1, or 2. n is 0, 1, 2, or 3. p is 0, 1, or 2. q is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9. s is 1, 2, 3, 4, 5, 6, 7, or 8. t is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or (18 years old) The immunogenic composition according to claim 1, comprising either or a pharmaceutically acceptable salt thereof.

3. The composition comprises more than 20 Streptococcus pneumoniae polysaccharide carrier protein conjugates. , each comprising a polysaccharide of a specific serotype of Streptococcus pneumoniae, according to claim 1 or 2, immunogenic group according to claim 1 or 2 Finished product.

4. The composition comprises more than 25 Streptococcus pneumoniae polysaccharide carrier protein conjugates. , each comprising a polysaccharide of a specific serotype of Streptococcus pneumoniae, according to claim 1 or 2, immunogenic group according to claim 1 or 2 Finished product.

5. The composition comprises 26 Streptococcus pneumoniae polysaccharide carrier protein conjugates, each However, it contains a polysaccharide of a specific serotype of Streptococcus pneumoniae conjugated to a carrier protein, and The Streptococcus pneumoniae serotypes are 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11. A, 12F, 14, 15A, de-O-acetylated 15B, 16F, 18C, 19A, 19F Claim 1, comprising 22F, 23A, 23B, 23F, 24F, 33F, and 35B Or the immunogenic composition described in 2.

6. The compound has the structure described in formula II: 【Chemistry 9】 (In the formula, R １ is, (C １ -C ６ ) is alkyl, and the above (C １ -C ６ Alkyl groups have -OH groups. B-O (CH ３ ) may be substituted with 1 to 4 substituents independently selected from ) R ２ is H, methyl or -O (CH ３ ) and R ３ Each occurrence of H, (C １ -C ４ ) alkyl, (C １ -C ４ ) Alkenil , (C １ -C ４ ) Alkinyl, or -O(C １ -C ４ ) is alkyl, and the above (C １ -C ４ ) alkyl, (C １ -C ４ ) Alkenil, (C １ -C ４ ) Alkinnil, or - O(C) １ -C ４ Alkyl groups are -OH and -O (CH ３ ) one that is selected independently of Alternatively, it may be substituted with two substituents. R ４ Each occurrence of H, (C １ -C ４ ) alkyl, (C １ -C ４ ) Alkenil , (C １ -C ４ ) Alkinyl, or -O(C １ -C ４ ) is alkyl, and the above (C １ -C ４ ) alkyl, (C １ -C ４ ) Alkenil, (C １ -C ４ ) Alkinnil, or - O(C) １ -C ４ Alkyl groups are -OH and -O (CH ３ ) one that is selected independently of Alternatively, it may be substituted with two substituents. R ５ teeth, 【Chemistry 10】 And, R ６ is, (C ６ -C ２０ ) alkyl, (C ６ -C ２０ ) alkenyl, and (C ６ -C ２０ ) Selected from alkynyl, and the (C ６ -C ２０ ) alkyl, (C ６ -C ２０ ) Al Kenil, and (C ６ -C ２０ Alkinyl is -OH, -O(C １ -C ４ ) alkyl, -O(C) １ -C ４ ) Alkenyl, -O(C １ -C ４ ) Alkynyl, chlorine, and fluorine They may be substituted with 1 to 6 substituents that are independently selected. Each occurrence of n is 4. The immunogenic composition according to claim 1, comprising either or a pharmaceutically acceptable salt thereof.

7. The compound has the structure described in formula IIa: 【Chemistry 11】 (In the formula, R １ is butyl, and the butyl may be substituted with one or two -OH groups. often, R ３ Each occurrence is independently H or -O (CH ３ ) and R ５ teeth, 【Chemistry 12】 And, R ６ is, (C １０ -C ２０ ) alkyl, (C １０ -C ２０ ) alkenyl, and (C １ ０ -C ２０ (Selected from Alkinil) The immunogenic composition according to claim 6, comprising either or a pharmaceutically acceptable salt thereof.

8. The composition comprises more than 20 Streptococcus pneumoniae polysaccharide carrier protein conjugates. , each comprising a polysaccharide of a specific serotype of Streptococcus pneumoniae, according to claim 6 or 7, immunogenic group according to claim 6 or 7 Finished product.

9. The composition comprises more than 25 Streptococcus pneumoniae polysaccharide carrier protein conjugates. , each comprising a polysaccharide of a specific serotype of Streptococcus pneumoniae, according to claim 6 or 7, immunogenic group according to claim 6 or 7 Finished product.

10. The composition comprises 26 Streptococcus pneumoniae polysaccharide carrier protein conjugates, each However, it contains a polysaccharide of a specific serotype of Streptococcus pneumoniae conjugated to a carrier protein, and The Streptococcus pneumoniae serotypes are 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11. A, 12F, 14, 15A, de-O-acetylated 15B, 16F, 18C, 19A, 19F Claim 6, consisting of 22F, 23A, 23B, 23F, 24F, 33F, and 35B Or the immunogenic composition described in 7.

11. The compound has the structure described in formula III: 【Chemistry 13】 (In the formula, R １ is, (C １ -C ６ ) is alkyl, and the above (C １ -C ６ Alkyl groups have -OH groups. B-O (CH ３ ) may be substituted with 1 to 4 substituents independently selected from ) R ２ is H, methyl or -O (CH ３ ) and R ３ Each occurrence of H, (C １ -C ４ ) alkyl, (C １ -C ４ ) Alkenil , (C １ -C ４ ) Alkinyl, or -O(C １ -C ４ ) is alkyl, and the above (C １ -C ４ ) alkyl, (C １ -C ４ ) Alkenil, (C １ -C ４ ) Alkinnil, or - O(C) １ -C ４ Alkyl groups are -OH and -O (CH ３ ) one that is selected independently of Alternatively, it may be substituted with two substituents. R ４ is, (C ６ -C ２０ ) alkyl, (C ６ -C ２０ ) alkenyl, and (C ６ -C ２０ ) Selected from alkynyl, and the (C ６ -C ２０ ) alkyl, (C ６ -C ２０ ) Al Kenil, and (C ６ -C ２０ Alkinyl is -OH, -O(C １ -C ４ ) alkyl, -O(C) １ -C ４ ) Alkenyl, -O(C １ -C ４ ) Alkynyl, chlorine, and fluorine They may be substituted with 1 to 6 substituents that are independently selected. n is 4. The immunogenic composition according to claim 1, comprising either or a pharmaceutically acceptable salt thereof.

12. The compound has the structure described in formula IIIa: 【Chemistry 14】 (In the formula, R １ is butyl, and the butyl may be substituted with one or two -OH groups. often, R ３ Each occurrence is independently H or -O (CH ３ ) and R ４ is, (C １０ -C ２０ ) alkyl, (C １０ -C ２０ ) alkenyl, and (C １ ０ -C ２０ (Selected from Alkinil) The immunogenic composition according to claim 11, or comprising a pharmaceutically acceptable salt thereof.

13. The composition comprises more than 20 Streptococcus pneumoniae polysaccharide carrier protein conjugates. The immunogen according to claim 11 or 12, each comprising a polysaccharide of a specific serotype of Streptococcus pneumoniae. sexual composition.

14. The composition comprises more than 25 Streptococcus pneumoniae polysaccharide carrier protein conjugates. The immunogen according to claim 11 or 12, each comprising a polysaccharide of a specific serotype of Streptococcus pneumoniae. sexual composition.

15. The composition comprises 26 Streptococcus pneumoniae polysaccharide carrier protein conjugates, each However, it contains a polysaccharide of a specific serotype of Streptococcus pneumoniae conjugated to a carrier protein, and The Streptococcus pneumoniae serotypes are 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11. A, 12F, 14, 15A, de-O-acetylated 15B, 16F, 18C, 19A, 19F Claim 1, comprising 22F, 23A, 23B, 23F, 24F, 33F, and 35B The immunogenic composition according to 1 or 12.

16. The compound has the structure described in formula IV: 【Chemistry 15】 (In the formula, R １ is, (C １ -C ６ ) is alkyl, and the above (C １ -C ６ Alkyl groups have -OH groups. B-O (CH ３ ) may be substituted with 1 to 4 substituents independently selected from ) R ２ is H, methyl or -O (CH ３ ) and R ３ Each occurrence of H, (C １ -C ４ ) alkyl, (C １ -C ４ ) Alkenil , (C １ -C ４ ) Alkinyl, or -O(C １ -C ４ ) is alkyl, and the (C １ -C ４ ) alkyl, (C １ -C ４ ) Alkenil, (C １ -C ４ ) Alkinyl, and -O (C １ -C ４ Alkyl groups are -OH and -O (CH ３ ) one that is selected independently Alternatively, it may be substituted with two substituents. R ４ Each occurrence is (C ６ -C ２０ ) alkyl, (C ６ -C ２０ ) Alkenil, and ( C ６ -C ２０ ) independently selected from alkynyl, and the (C ６ -C ２０ ) alkyl, (C ６ -C ２０ ) alkenyl, and (C ６ -C ２０ Alkinyl is -OH, -O(C １ - C ４ ) alkyl, -O(C １ -C ４ ) Alkenyl, -O(C １ -C ４ ) Alkinyl, Chloride Alternatively, it may be substituted with 1 to 6 substituents independently selected from fluorine. n is 4. The immunogenic composition according to claim 1, comprising either or a pharmaceutically acceptable salt thereof.

17. The compound has the structure described in formula IVa: 【Chemistry 16】 (In the formula, R １ is butyl, and the butyl may be substituted with one or two -OH groups. often, R ３ Each occurrence is independently H or -O (CH ３ ) and R ４ Each occurrence is (C １０ -C ２０ ) alkyl, (C １０ -C ２０ ) Alkenil, oh bi (C １０ -C ２０ (Selected independently of Alkinnil) The immunogenic composition according to claim 16, comprising a pharmaceutically acceptable salt thereof.

18. The composition comprises more than 20 Streptococcus pneumoniae polysaccharide carrier protein conjugates. The immunogen according to claim 16 or 17, each comprising a polysaccharide of a specific serotype of Streptococcus pneumoniae. sexual composition.

19. The composition comprises more than 25 Streptococcus pneumoniae polysaccharide carrier protein conjugates. The immunogen according to claim 16 or 17, each comprising a polysaccharide of a specific serotype of Streptococcus pneumoniae. sexual composition.

20. The composition comprises 26 Streptococcus pneumoniae polysaccharide carrier protein conjugates, each However, it contains a polysaccharide of a specific serotype of Streptococcus pneumoniae conjugated to a carrier protein, and The Streptococcus pneumoniae serotypes are 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11. A, 12F, 14, 15A, de-O-acetylated 15B, 16F, 18C, 19A, 19F Claim 1, comprising 22F, 23A, 23B, 23F, 24F, 33F, and 35B The immunogenic composition described in 6 or 17.

21. The aforementioned compound, (N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[ 4,3-d]pyrimidine-2-yl(methyl)-3,5-dimethoxyphenyl)piperazi (n-1-yl)-5-oxopentyl) stearamide, (S)-N-(5-(4-(4-((5-amino-7-((1-hydroxypentane- 2-yl)amino)-2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)- 3,5-Dimethoxyphenyl)piperazine-1-yl)-5-oxopentyl)stear Mido, N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Il)-5-oxopentyl) stearamide, N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Iyl)-5-oxopentyl)tetradecaneamide, N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Iyl)-5-oxopentyl)oleamide, (9Z,12Z)-N-(5-(4-(4-((5-amino-7-(butylamino)- 2H-pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3-methoxyphenyl (Piperadin-1-yl)-5-oxopentyl)octadeca-9,12-dienamide 、 N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 [3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)-1,4-diaze Pan-1-yl)-5-oxopentyl) stearamide, N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperidine-1- (Il)-5-oxopentyl) stearamide, N-(5-(3-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)azetidine-1- (Il)-5-oxopentyl) stearamide, 1-(4-((5-amino-7-(butylamino)-2H-pyrazolop[4,3-d]py Limidine-2-yl(methyl)-3-methoxyphenyl)-N-(3-stearamidopro (Pill) Piperidine-4-carboxamide, (1s, 3s)-3-(2-(4-(4-((5-amino-7-(butylamino)-2 H-pyrazolo[4,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl) Piperazine-1-yl)-2-oxoethyl)-N-hexadecylcyclobutane-1-ca Ruboxamide, N-(3-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Iyl)-3-oxopropyl) stearamide, N-(7-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Il)-7-oxoheptyl) stearamide, N-(3-(2-(4-(4-((5-amino-7-(butylamino)-2H-pyrazo Ro[4,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl(piperazine) (-1-yl)-2-oxoethyl)cyclobutyl)stearamide, N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Iyl)-4,4-dimethyl-5-oxopentyl) stearamide, N-(5-(4-(4-((5-amino-7-(butylamino)-3-methyl-2H- Pyrazolo[4,3-d]pyrimidine-2-yl)methyl)3-methoxyphenyl)pipet Radin-1-yl)-5-oxopentyl) stearamide, (9Z,12Z)-N-(4-((4-((5-amino-7-(butylamino)-2H -Pyrazolo[4,3-d]pyrimidine-2-yl)methyl)-3,5-dimethoxybenzyl (Methyl)aminobutyl)octadeca-9,12-dienamide, N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3 -d]pyrimidine-2-yl(methyl)-3,5-dimethoxybenzyl(methyl)amide (no)butyl)tetradecaneamide, N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3 -d]pyrimidine-2-yl(methyl)-3,5-dimethoxybenzyl(methyl)amide (no)butyl)oleamide, N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3 -d]pyrimidine-2-yl(methyl)-3,5-dimethoxybenzyl(methyl)amide (N)Butyl)Stearamide, N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3 -d]pyrimidine-2-yl(methyl)-3,5-dimethoxybenzyl(methyl)amide (no)-4-oxobutyl) stearamide, (6Z, 9Z, 28Z, 31Z) - Heptatria Contour - 6, 9, 28, 31 - Tetra En-19-yl(4-((4-((5-amino-7-(butylamino)-2H-pyrazo Ro[4,3-d]pyrimidine-2-yl(methyl)-3,5-dimethoxybenzyl)(Me Chill aminobutyl carbamate, 4-(4-((5-amino-7-(butylamino)-2H-pyrazolopyrazolo[4,3-d]py Limidine-2-yl(methyl)-3-methoxyphenyl)-N-(3-stearamidopro (Pill) Piperazine-1-carboxamide, and 3-Stearamidopropyl 4-(4-((5-Amino-7-(butylamino)-2H- Pyrazolo[4,3-d]pyrimidine-2-yl)methyl)3-methoxyphenyl)pipet Radin-1-carboxylate, or selected from a pharmaceutically acceptable salt thereof, as described in any one of claims 1 to 20. The immunogenic composition listed.

22. The aforementioned compound, N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4 ,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl)piperazine-1- (Il)-5-oxopentyl) stearamide, The immunoassay according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof. genic composition.

23. (iii) Sorbitan trioleate (SPAN-85) and (iv) Polysorbate -20 (PS-20) or polysorbate-80 (PS-80) and (v) squalene The immunogenic composition according to any one of claims 1 to 22, further comprising the above.

24. The aforementioned compound is N-(5-(4-(4-((5-amino-7-(butylamino)-2H -Pyrazolo[4,3-d]pyrimidine-2-yl(methyl)-3-methoxyphenyl) Perazin-1-yl)-5-oxopentyl) stearamide, or its pharmaceutically acceptable form The immunogenic composition according to claim 23, which is a salt.

25. The immunogenic composition according to claim 24, wherein the composition comprises PS-20.

26. The composition comprises more than 20 Streptococcus pneumoniae polysaccharide carrier protein conjugates. , each containing a polysaccharide of a specific serotype of Streptococcus pneumoniae, as described in any one of claims 23 to 25. The immunogenic composition listed.

27. The composition comprises more than 25 Streptococcus pneumoniae polysaccharide carrier protein conjugates. , each containing a polysaccharide of a specific serotype of Streptococcus pneumoniae, as described in any one of claims 23 to 25. The immunogenic composition listed.

28. The composition comprises 26 Streptococcus pneumoniae polysaccharide carrier protein conjugates, each However, it contains a polysaccharide of a specific serotype of Streptococcus pneumoniae conjugated to a carrier protein, and The Streptococcus pneumoniae serotypes are 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11. A, 12F, 14, 15A, de-O-acetylated 15B, 16F, 18C, 19A, 19F Claim 2, comprising 22F, 23A, 23B, 23F, 24F, 33F, and 35B. An immunogenic composition according to any one of items 3 to 25.

29. (vi) The present invention further comprising a pharmaceutically acceptable carrier, as described in any one of claims 1 to 28. An immunogenic composition.

30. The carrier protein is CRM197, according to any one of claims 1 to 29. Immunogenic composition.

31. The concentration of the compound is 0.1 μg / mL to 100 μg / mL, and the concentration of SPAN-85 is The concentration ranges from 0.01 mg / mL to 50 mg / mL, with PS-20 or PS-80 concentrations of 0. The concentration ranges from 0.01 mg / mL to 50 mg / mL, with squalene concentrations ranging from 0.02 mg / mL to 20 mg / mL. An immunogenic composition according to any one of claims 23 to 30, wherein the concentration is mg / mL.

32. A method for treating or preventing pneumococcal disease in human patients, the method according to claims 1 to 31. A method comprising administering an immunogenic composition described in any one of the paragraphs to the patient.

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